Deininger, Michael W.

Abstract Introduction: Despite advent of multiple tyrosine kinase inhibitors (TKIs) and newer treatment methods for AML and ALL, the outcomes of patients (pts) with chronic myeloid leukemia in blast phase (CML-BP) remain poor. Consensus guidelines on treatment of CML-BP are scarce. A recent study from the European leukemia network blast phase registry on 240 pts reported marked heterogeneity in treatment patterns and lack of an accepted standard. Hence, we undertook this study through the H Jean Khoury Cure CML Consortium (HJKC3) to describe the treatment patterns and outcomes of pts with CML-BP in the US. Methods: This is a multi-institution, retrospective study. IRB approval was obtained at each institution and data sharing agreements were executed. All pts diagnosed with CML-BP based on modified MD Anderson Criteria (≥30% blasts in the blood or bone marrow or extramedullary (EM) disease) from 2010 to 2025 were included. Categorical variables were compared using Chi-square test. Overall survival (OS) was calculated from time of diagnosis of CML BP to death from any cause. Event free survival (EFS) was calculated from date of best response to event (death or relapse). Results: Of the 283 pts with CML-BP, 96 (33.9%) were female and 187 (66.1%) were males. At the time of diagnosis, 183 (64.6%) had CML-CP, 21 (7.4%) pts had CML-AP and 79 (27.9%) pts had de-novo CML-BP. For the 204 pts that were initially diagnosed with CML-CP or CML-AP, the median time to progression to CML-BP was 22.5 months (1-207 months). Median age at diagnosis of CML-BP was 50 years (range 16-86 years). EM disease was present in 78 (27.6%) pts (38 myeloid sarcoma, 30 central nervous system and 10 skin). Blasts were of myeloid phenotype in 168 (59.4%), lymphoid in 103 (36.4%) and mixed in 9 (3.2%) pts. The bcr-abl protein was p210 in 229 (80.9%), p190 in 8 (2.8%) and p230 in 2 (0.7%) pts. ABL kinase domain mutation was seen in 42.1% (80/190) pts, with T315I being the most common (n=32), followed by E255K (n=16). Next generation sequencing was performed in 117 pts. The most common mutations were ASXL1 (n=27), RUNX1 (n=14), BCOR (n=4), DNMT3A (n=4) and BCORL1 (n=3). Of the 283 pts, 269 underwent CML-BP directed therapy. 63 (23.4%) pts were treated with TKI monotherapy, 184 (68.4%) pts were treated with a combination of chemotherapy (chemo) and TKI and 22 (8.2%) pts were treated with chemo alone. Response rate after CML-BP directed therapy was 75.3% (n=213). Best response was return to CML-CP in 49 pts, CHR with PCyR in 18 pts, CCyR in 31 pts, MMR in 31 pts, MR4 in 18 pts, MR4.5 in 19 pts and MR5 in 47 pts. Rate of response with 2G and ponatinib was significantly better than imatinib (85.3% and 77.3% vs 63.6%; p=0.04). 149 (55.4%) pts proceeded to alloSCT. Of the 213 pts that responded, 59 (27.7%) relapsed. At a median follow-up of 47 months, the median OS for all pts was 19.7 months (95% CI: 16.3-40.2 months), with 5-year OS rate of 38% (95% CI: 32-45%). Pts with myeloid phenotype had a significantly lower OS compared to lymphoid and mixed phenotype (Median OS 14.9 vs 45.9 and 31.1 months respectively; p=0.02). OS of pts that were treated with a combination of TKI and chemo was significantly longer compared to pts treated with TKI or chemo alone (52.9 vs 16.1 or 7.5 months; p<0.0001). Dasatinib (n=99; 34.9%) and ponatinib (n=97; 34.3%) were the most used TKIs followed by imatinib (n=23; 8.1%), nilotinib (n=21; 7.4%), bosutinib (n=8; 2.8%) and asciminib (n=3; 1.1%). Pts treated with ponatinib had a numerically longer OS compared to 2G-TKI and imatinib, however this was not statistically significant (40.1 vs 30.6 and 20.3 months; p=0.52). EFS for pts treated with ponatinib was significantly longer compared to 2G-TKI or imatinib (25.9 vs 17.6 and 15.9 months; p=0.03). In a landmark analysis, pts that underwent alloSCT within 6 months of diagnosis had a significantly longer OS compared to those who did not (69.3 vs 16.0 months; p=0.006). Conclusion: CML-BP continues to have poor prognosis. Treatment is heterogenous involving various combinations of TKI and chemo. In our analysis, treatment with 2G-TKI or ponatinib led to better responses. CML-BP with myeloid phenotype had worse OS. Treatment with ponatinib was associated with a numerically longer OS and significantly longer EFS compared to 2G-TKI and imatinib. In addition, treatment with chemo in combination with TKI and alloSCT led to improved OS.

Background: The BeatAML Master Trial (BAMT) began in 2016 with a goal of determining the feasibility of a precision-medicine approach in treating acute myeloid leukemia (AML) in older adults ≥ 60 years of age where outcomes are poor. At the time, standard of care (SOC) for older patients with AML was intensive 7+3 chemotherapy (cytarabine + daunorubicin) if fit and hypomethylating agents (HMA: azacitidine or decitabine) if unfit. Besides confirming the feasibility, the early results (2019) from the Master Trial suggested that patients who received therapy on one of the sub-studies had a lower early death rate and superior overall survival compared to patients receiving off-protocol SOC, which was primarily single-agent HMA at the time. Since then, the 2019 approval of venetoclax (ven) + azacitidine for older unfit AML patients has been transformative and emerged as the SOC. Using data from the BAMT from 2016-2024, we suggest that knowing the comprehensive genomic profile of AML at the time of diagnosis is still beneficial in determining therapy that would lead to the optimal outcome and that development of targeted therapies and combination regimens with ven/HMA is still needed. Methods: This is a retrospective analysis of 1096 patients who consented and enrolled on the BAMT (NCT03013998) from Nov 2016 through Jun 2024. Patients ≥ 60 years with newly diagnosed AML were included. Patients underwent therapy on a BeatAML sub-study based on their genetics (N=433) or treatment off-protocol (N=663). We divided the patients according to what therapy they received: (1) Non-Intensive (Off-Protocol, N=121), (2) Ven/HMA (Off-Protocol, N=234), (3) Non-Intensive (Sub-Study, N=407), (4) Intensive (Sub-Study, N=26), and (5) Intensive (Off-Protocol, N=155). 94 patients received no treatment and 59 were unknown. Non-intensive therapies included primarily targeted agents or non-ven combinations. We analyzed baseline characteristics and demographics, overall survival (OS), and the impact of allogenic stem cell transplant (SCT). OS, using Kaplan-Meier method, was measured from the start of therapy to all-cause death, censoring patients at last follow-up. Results: Characteristics and demographics were similar between Groups 1, 2 and 3. Group 4 and 5 were treated with intensive chemotherapy and their characteristics are reflective of younger/fit patients appropriate for the intensive regimen. Groups 4 and 5 also had the longest median OS (mOS) of 40.2 months (95% CI: 13.9-not reached (NR)) and 42.3 months (95% CI: 25.1-NR) respectively. Group 3, which included patients treated with a non-intensive, targeted therapy on a sub-study, had an mOS of 14.0 months (95% CI: 12.3-16.7), which was similar to Group 2, treated with Ven/HMA, that had an mOS of 13.2 months (95% CI: 10.9-16.3). Lastly, patients in Group 1, who were treated primarily with HMA monotherapy, did poorly in comparison, with an mOS of 6.0 months (95% CI: 3.3-10.1). Additionally, we looked at the cumulative incidence rate (CIR) of SCT. The CIR in 12 months of Group 1 was 9.8% (95% CI: 6.9-13.4), Group 2: 5.4% (95% CI: 2.2-10.7), Group 3 and 4 combined: 35.0% (95% CI: 628.1-42.1), and Group 5: 13.1% (95% CI: 6.9-13.4). In a multi-variable analysis, after adjusting for typical favorable risk factors like NPM1 mutations and core binding factor, SCT was highly significant (p<0.0001) in improving OS with a hazard ratio of 0.23 (95% CI: 0.16-0.32), and Group 3 performed similarly to Group 2 (p=0.20). Conclusions: First, our results suggest that it is clinically relevant to correctly identify whether an intensive chemotherapy, targeted-therapy, or ven/HMA regimen is best suited for older AML patients, for which a precision-medicine trial is ideal for. Secondly, in this group of patients, our results show that patients treated with a non-intensive targeted therapy (Group 3) has a similar mOS to those treated with ven/HMA (Group 2). Especially after controlling for patient characteristics, patients in Group 2 performed similar to those in Group 3 (p=0.20). Patients in Group 3 were treated on Beat AML sub-studies which included targeted therapy alone or with non-venetoclax combinations, which is a strong rationale for continued development of targeted agents to optimize toxicity and quality of life with similar survival. Lastly, this data also supports the need to improve the ven/HMA SOC by developing combination regimens with targeted agents to further improve outcomes.

Background: Mutations of isocitrate dehydrogenase (IDH) are recurrent in acute myeloid leukemia (AML) and the prevalence increases with age. The prognostic impact of IDH1 and IDH2 mutations remains controversial. IDH inhibitors are small molecules that bind within the IDH enzymatic active site, blocking aberrant 2-hydroxyglutarate production and inducing myeloid differentiation. While they can lead to differentiation syndrome, they generally have a more favorable side-effect profile, making them an attractive option for older patients. We aimed to describe the prevalence and prognostic impact of IDH mutations in newly diagnosed (ND) AML patients ≥ 60 years in a large cohort of patients treated on a Leukemia and Lymphoma Society-sponsored trial. Methods: We performed a retrospective observational analysis including patients ≥ 60 years with ND AML who were enrolled on the Beat AML clinical trial (NCT03013998) before May 10, 2023. Patients were treated with a variety of treatment regimens. Cytogenetic analysis and next-generation sequencing (FoundationOne®Heme) were obtained. Mutations were considered present at any detectable VAF. Cox proportional hazard models were used to describe the relative risk of each variable on death over time from the date of trial inclusion. Results: A total of 1023 patients with ND AML were identified. Patients had a median age of 72 (range 60-92) years and the majority were non-Hispanic White (83.2%), and male (57.6%). Ninety-nine (9.7%) patients were IDH1MUT, 193 (18.9%) patients were IDH2MUT including 10 (1.0%) patients with a co-occurring IDH1 and IDH2 gene mutations. Both IDH1MUT and IDH2MUT were associated with 2022 ELN favorable-risk (26.3% and 22.3% for IDH1 and IDH2 respectively, vs 15.5% overall (P<0.001)). IDH1MUT significantly co-occurred with DNMT3AMUT (42.4%), NPM1MUT (44.4%) and less frequently with TP53MUT (10.1%) (P<0.001 for all). IDH2MUT was associated with DNMT3AMUT (35.8%), NPM1MUT (31.1%), SRSF2MUT (38.3%), and less frequently with TET2MUT (6.7%) and TP53MUT (9.3%) (P<0.001 for all). Normal karyotype was higher in IDH1MUT (P<0.001) and IDH2MUT (P<0.001), whereas complex karyotype (P<0.001 for both) and core-binding factor AML (P=0.047, P=0.015) were lower in IDH1MUT and IDH2MUT. To evaluate the impact of IDH mutations in patients ≥ 60 years, we focused on patients evaluable for outcome treated with lower-intensity therapy (LIT) (N=674), and intensive chemotherapy (IC) (N=178), separately. Among the LIT treated patients, 96 patients received treatment with an IDH inhibitor, and 237 patients received a hypomethylating agent (HMA) plus venetoclax. For patients treated with LIT, the hazard ratios (HRs) of death over time were 0.58 [95% CI 0.47-0.72; P<0.002], 0.81 [95% CI 0.59-1.13; P=0.214] and 0.56 [95% CI 0.44-0.72; P<0.001] for IDHMUT, IDH1MUT, IDH2MUT respectively. Among patients receiving IC, the HRs were 1.05 [95% CI 0.68-1.69; P=0.777], 0.70 [95% CI 0.31-1.61; P=0.406] and 1.27 [95% CI 0.77-2.1; P=0.352] for IDHMUT, IDH1MUT, and IDH2MUT respectively. The HR of death for IDH1MUT patients treated with LIT with the addition of an IDH1 inhibitor (N=24) was significantly lower (HR 0.47 [95% CI 0.24-0.92; P=0.027] vs IDH1MUT patients treated without an IDH1 inhibitor, while an IDH2 inhibitor did not change survivial outcomes in patients with IDH2MUT (N=71). Discussion: To our knowledge this is the largest retrospective study characterizing the prevalence of IDH mutations in patients ≥ 60 years with AML. We demonstrated that IDH mutations were detected in ~27% of older patients with AML. Although there could have been selection bias as the Beat AML study had separate IDHMUT study arms, these findings are concordant with other studies showing an increase in frequency of IDH mutations with age. IDH2MUT was associated with a lower HR of death among patients treated with LIT, which was not seen in patients receiving IC. The high prevalence of IDH mutations suggests that IDH inhibitors used as single agents or in combination with lower-intensity therapies are an important class of drugs for this older patient population as they are generally well tolerated, that need further investigation.

Introduction: Despite advent of multiple tyrosine kinase inhibitors (TKIs) and newer treatment methods for both AML and ALL, the outcomes of patients (pts) with chronic myeloid leukemia in blast phase (CML-BP) remain poor. Consensus guidelines on treatment of CML-BP are scarce. A recent study from the European leukemia network (ELN) blast phase registry reported outcomes of 240 CML-BP pts. They also reported marked heterogeneity in treatment patterns and lack of an accepted standard. Hence, we are undertaking this study through the H Jean Khoury Cure CML Consortium (HJKC3) to study the treatment patterns and outcomes of pts with CML-BP in the US. Methods: This is a multi-institution, retrospective study. IRB approval was obtained at each institution separately and data sharing agreements were executed. All pts diagnosed with CML-BP based on modified MD Anderson Criteria (≥30% blasts in the blood or bone marrow or extramedullary (EM) disease) from 2010 to 2024 were included. Categorical variables were compared using the Chi-square test. Overall survival (OS) was calculated from the time of diagnosis to death from any cause. Survival probabilities were computed using the Kaplan-Meier method and compared with the log-rank test. Results: Of the 72 pts with CML-BP included in this analysis, 29 (40.3%) were female and 43 (59.7%) were males. At the time of diagnosis, 36 (50%) had CML-CP (chronic myeloid leukemia in chronic phase), 11 (15.3%) pts were diagnosed with CML-AP (accelerated phase CML) and 25 (34.7%) pts with de-novo CML-BP. For the 47 pts that were initially diagnosed with CML-CP or CML-AP, the median time to progression to CML-BP was 26 months (1-207 months). Median age at diagnosis of CML-BP was 54 years (range 21-86 years). EM disease was present in 17 (23.6%) pts (7 myeloid sarcoma, 5 central nervous system and 5 skin) with 3 pts presenting with EM disease only. Blasts were of myeloid phenotype in 41 (56.9%), lymphoid in 29 (40.3%) and mixed in 2 (2.8%) pts. The bcr-abl protein was p210 in 59 (81.9%), p190 in 5 (6.9%) and p230 in 1 (1.4%) pt. Four pts had prior allogeneic stem cell transplant (alloSCT) for CML-CP. Of the pts who had an ABL kinase domain mutation tested, 42.9% (18/42) pts were found to have an ABL kinase domain mutation. The most common TKD mutation was T315I (n=6). Next generation sequencing was performed in 32 pts. The most common mutations were ASXL1 (n=10), RUNX1 (n=4), BCOR (n=2), BCORL1 (n=2), DNMT3A (n=2) and 1 each in CSF3R, KMT2A, EZH2, NF1 and TP53. Of the 72 pts, 68 underwent CML-BP directed therapy. While only 9 (13.2%) pts were treated with TKI alone (4 dasatinib, 2 imatinib, 2 ponatinib and 1 asciminib), 54 (79.4%) pts were treated with a combination of chemotherapy with TKI (24 dasatinib, 13 ponatinib, 9 imatinib, 6 nilotinib, 1 bosutinib and 1 asciminib), and 5 (7.4%) pts were treated with chemotherapy alone. The response rate after CML-BP directed therapy was 72.1% (n=49). Best response was return to CML-CP in 17 pts, CHR with PCyR in 1 pt, CCyR in 11 pts, MMR in 5 pts, MR4 in 4 pts, MR4.5 in 5 pts and MR5 in 6 pts. Rate of response with third and second generation TKI was significantly better than first generation TKI (80% and 77.1% vs 36.3%; p=0.02287). 30 (44.1%) pts proceeded to alloSCT. Of the 49 pts that responded, 16 (32.6%) relapsed. The median time to relapse was 5 months (range 1-46 months). At a median follow up of 57 months, the median OS for all pts was 18 months. There was no difference in OS based on blast phenotype (14 months for myeloid, 21 for lymphoid and 7.5 for mixed; p=0.1185), initial diagnosis (38 months CP-CML, 13 for CML-AP and 16 for de-novo BP pts; p=0.6380), or TKI (13 months for first generation, 20 for second and not reached for third generation TKI; p=0.1729). The OS of pts that were treated with a combination of TKI and chemotherapy was significantly longer compared to pts treated with TKI or chemo alone (28 vs 13 or 4.5 months; p=0.0003). Of the 32 pts that responded, OS for pts that underwent alloSCT was significantly longer compared to pts that did not (not reached vs 14 months; p= 0.0022). Conclusion: CML-BP continues to have a dismal prognosis. Treatment is heterogenous involving various combinations of TKI and chemotherapy. In our analysis, treatment with second or third generation TKI led to better responses. In addition, treatment with chemotherapy in combination with TKI and alloSCT led to improved OS. Updated results from further multi-institution analysis will be presented at the meeting.

Background: Chromosomal rearrangements involving the KMT2A gene and mutations involving the nucleophosmin (NPM1) gene have been associated with response to menin inhibitors in multiple studies of acute myeloid leukemia (AML) patients characterized by these genetic alterations. Both alterations are more common in younger AML patients and those with NPM1 mutations historically perform better. However, the prevalence and outcomes of older (≥60 years) AML patients with these alterations who are treated with current therapies is less well understood. We present results from the Beat AML Master Trial (BAMT) that analyze the outcomes of this large, but less common subset of patients in an older AML population. Methods: Patients were consented and enrolled on this precision medicine-based Beat AML Master Trial (NCT03013998) from November 2016 to June 2024. Patients were included in this analysis if they harbor either the classic NPM1 mutation or a KMT2A rearrangement (over 10 different gene partners). Additionally, 2 patients with a NUP98 rearrangement were included with the KMT2A cohort as they are known to have similar biology in terms of menin dependence. These patients were treated with the following therapies: a sub-study specific targeted therapy for the dominant clone, venetoclax + hypomethylating agent (Ven/HMA), intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. Clinical/genetic characteristics and median overall survival (OS) were analyzed in each group separately. Overall survival (OS) was calculated from master consent and estimated using the Kaplan-Meier method. Results: Of 1096 AML patients enrolled on the BAMT, 246 patients had either an NPM1 (N=207, 18.9%) or KMT2A (N=39, 3.6%) genetic alteration. The baseline characteristics for the NPM1 cohort were median age 72 years (range: 60-92), 50% female, and ECOG performance status: 0-16%, 1-58%, 2-25% and 3-1%. Additional disease characteristics include treatment related AML at 11% and complex karyotype (≥3 abnormalities) at 3%. Median OS for the entire NPM1 cohort was 18.4 months (95% CI: 14.2-24.7). Patients were treated on a sub-study (35%), Ven/HMA (19%), IC (26%), NIT (8%) or no treatment (9%). Between treatment groups, median OS was 21 months (95% CI: 12.8-31.7) for those treated on a sub-study, 22 months (95% CI: 12.6-not reached (NR)) for Ven/HMA, 41.6 months (95% CI: 18.2-NR) for IC, and 6.3 months (95% CI: 1.3-23) for NIT, which was significantly different (p<0.0001). The baseline characteristics for the KMT2A cohort were median age 69 years (range: 60-88), 44% female, and ECOG performance status: 0-19%, 1-45%, 2-35% and 3-0%. Treatment related AML occurred in 23% of patients and complex karyotype in 31%. Median OS for the KMT2A cohort was 6.5 months (95% CI: 3.6-31.6). Patients were treated on a sub-study (38%), Ven/HMA (15%), IC (15%), NIT (15%), or no treatment (5%). Between treatment groups, median OS was 31.6 months (95% CI: 3.2-NR) for sub-study, 5.0 months (95% CI: 3.0-NR) for Ven/HMA, 12.7 months (95% CI: 4.9-NR) for IC, and 2.9 months (95% CI: 1.5-NR) for NIT, which was also significantly different (p<0.0001). Conclusions: In this cohort of older AML patients who possess NPM1 or KMT2A mutations, initial demographics and clinical characteristics upon presentation are as expected. Within each cohort and depending on the type of therapy received, there were interesting differences in survival. Median OS was the highest for the NPM1 cohort that received IC while the KMT2A cohort had the highest median OS when enrolled on a KMT2A targeted sub-study; a finding that supports precision-based medicine for this high-risk KMT2A group characterized by poor outcomes. As menin inhibitor combinations with induction chemotherapy or Ven/HMA move to the frontline setting, we anticipate seeing significant improvement in outcomes for AML patients in both of these genomic subsets. Further multivariable analysis will be performed to validate treatment effect on OS. Our analyses for these two cohorts also provide valuable outcome benchmarks for the design of future precision oncology studies that seek to improve survival in these subsets of older AML patients.

Background and Significance: Systemic mastocytosis (SM) is a rare heterogeneous disease characterized by the aberrant accumulation of neoplastic mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Despite improvement in disease control with approval of tyrosine kinase inhibitors (TKIs), there is still unmet need for improved tolerability and efficacy in AdvSM treatments. Bezuclastinib, an oral and selective type 1 TKI that potently inhibits KIT D816V, is being studied in patients diagnosed with AdvSM in the Apex study (NCT04996875). Results from the Part 1 dose optimization portion of Apex were presented previously. Part 1 randomized 32 patients 1:1:1:1 to receive bezuclastinib at 50, 100, or 200 mg BID or 400 mg QD. Initial results from the Part 1 dose optimization portion of the Apex trial in patients with AdvSM demonstrated encouraging safety profile and signs of clinical activity, as well as deep reductions across biomarkers of MC burden including bone marrow MC burden, serum tryptase levels, and KIT D816V variant allele fraction (VAF). In addition, 94%, 93%, and 100% of patients demonstrated ≥50% reduction in serum tryptase, KIT D816V VAF, and bone marrow MC burden, respectively. Exposure achieved with 100 mg BID of bezuclastinib original formulation resulted in optimal efficacy and safety outcomes. 150 mg QD of an optimized formulation is expected to deliver bezuclastinib exposures consistent with the 100 mg BID of the original formulation. Part 2 is further evaluating the efficacy and safety of bezuclastinib in patients with AdvSM at the selected Part 2 dose of 150mg QD of the optimized formulation. Study Design and Methods: Apex is a multicenter, Phase 2 open-label study of bezuclastinib in patients with AdvSM as defined per the WHO criteria. Enrollment includes previously treated and treatment-naïve patients. Part 2 is enrolling approximately 65 patients including up to 15 patients without measurable mIWG C-findings. The Part 2 expansion portion of the Apex study is designed to evaluate the efficacy and safety of bezuclastinib in patients with AdvSM, including ASM, SM-AHN, or MCL. Key eligibility criteria include measurable disease (centrally adjudicated) according to modified IWG-MRT-ECNM criteria and clinically acceptable laboratory values including platelet count ≥50,000/µL. The primary efficacy endpoint of Part 2 is overall response rate (ORR = complete response [CR] + complete remission with partial hematologic recovery [CRh] + partial response [PR] + clinical improvement [CI]) per mIWG-MRT-ECNM criteria according to mIWG-MRT-ECNM response criteria and will be confirmed by a Central Response Review Committee. Secondary endpoints include further characterization of safety and tolerability, pure pathologic response, biomarker response (including changes in bone marrow MC burden, serum tryptase level, and KIT D816V mutational burden), duration of response, time to response, progression-free survival, and overall survival (OS). Apex Part 2 is actively enrolling. Study sites are enrolling in North America, Asia-Pacific, and Europe. In addition, a high-risk SM-AHN sub-study assessing the safety and feasibility of the combination of bezuclastinib 150 mg QD and azacitidine may enroll up to 20 patients who are currently receiving or indicated for azacitidine and have biopsy-proven SM with an associated high- or very high-risk myeloid neoplasm. Patients with SM-AHN from Part 1 or Part 2 who have demonstrated AHN progression may enroll in an additional rollover cohort to receive bezuclastinib with concomitant azacitidine or hydroxyurea.

Abstract Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A “mutation score” was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: −1 to 0 points (“Beat-AML intermediate”) vs 1+ points (“Beat-AML adverse”). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined “Beat-AML favorable-risk” group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making.

Background: First-line therapies for chronic-phase (CP) CML include the tyrosine kinase inhibitors(TKIs) dasatinib, nilotinib, bosutinib or imatinib, while ponatinib and asciminib are indicated only in later lines. There are typically high response rates to first-line therapy in CP-CML, with responses to second- and third-line therapy lower and highly dependent on the specific TKI. Our goal in this study is to evaluate the role of ponatinib in the treatment of patients with CML using data from routine clinical practice. Study design and methods: Data will come from the H. Jean Khoury Cure CML Consortium (HJKC3) CML registry, a North American multi-site research database. Participating sites include the HJKC3 members (curecml.org). Patient inclusion criteria include a diagnosis CML in chronic phase, receiving second line therapy after initial therapy with a second generation TKI (dasatinib, nilotinib, or bosutinib) or receiving third or later line TKI therapy for CML. Participating patients provide consent to collect their data both retrospectively and prospectively for 1 year. Clinical data, including toxicities and complications of TKI therapy, are abstracted from the electronic health record. Participating patients are invited to complete a questionnaire to assess health-related quality of life. Data are managed using REDCap, a secure web application. Study Objectives: The primary objective is to compare the outcome of patients treated with ponatinib vs. other TKIs as second or later line therapy. Secondary objectives are to evaluate patient-reported outcomes (PRO) for CML treated with second or later line therapy and to determine if there are any patient or disease characteristics that can predict outcomes. Statistical plan for clinical outcomes: Descriptive statistics will be used to compare baseline demographic characteristics. Categorical variables will be compared using the Chi-square test. Continuous variables will be compared using ANOVA. Overall survival will be calculated from the time of diagnosis to death from any cause and patients will be censored if they were alive at the last follow-up. Survival probabilities will be computed using the Kaplan-Meier method and compared with the log-ranktest. Cox regression analyses will be used to determine significant factors that influence survival, and hazard ratios with 95% confidence intervals will be presented. Event free survival (EFS) and transformation free survival (TFS) will be calculated for patients. For EFS, loss of complete hematologic remission, loss of major cytogenetic response, progression to accelerated or blast phase, or death from any cause at any time will be considered an event. For TFS, transformation to accelerated or blast phase while on therapy or death on study will be considered an event. Statistical plan for PRO: Different PRO domains will be analyzed separately (for example, depression separate from fatigue, etc.). Descriptive statistics for each PRO measure will be reported and compared to previously published studies. Differences by treatment type will be evaluated.

Background. Some patients who present with clinical features consistent with idiopathic hypereosinophilic syndrome (HES; absolute eosinophil count (AEC) ≥1.5 x 10 9/L with related end organ damage) are ultimately diagnosed with a myeloid neoplasm. Although FIP1L1::PDGFRA is the most common molecular abnormality in this setting, many other fusion genes, point mutations and cytogenetic abnormalities have been implicated in driving primary (neoplastic) eosinophilia. Given the poor prognosis of these disorders in the absence of treatment and the availability of targeted therapies for many of the driver mutations, it is becoming increasingly important to rapidly identify the underlying genetic alteration. In this regard, the expense and variable sensitivity of molecular diagnostic tests remains problematic. Although clinical features have been reported to distinguish between PDGFRA-associated myeloid neoplasms and D816V KIT-positive systemic mastocytosis with hypereosinophilia, little is known about the clinical phenotypes of other subsets of patients. This multicenter retrospective study aimed to assemble a large cohort of patients with HES secondary to a myeloid neoplasm to explore the utility of clinical and laboratory features in predicting the underlying molecular abnormality. Methods. Retrospective, de-identified data from 16 centers were collected via an online Research Electronic Data Capture repository. Patients and associated data were obtained from in-house research databases and/or electronic medical record searches at each site. Clinical and laboratory data were entered in accordance with local Institutional Review Boards. Inclusion criteria were peripheral blood hypereosinophilia (AEC >1.5 x 10 9/L) on at least two occasions and one of the following: ≥1 confirmed genetic abnormality recurrently associated with primary myeloid neoplasms, other evidence of clonal eosinophilia, or increased blasts (≥2% in the blood or >5% but <20% in the marrow). Patients with acute myeloid leukemia were excluded. Results. A total of 277 patients followed between 1990 and 2022 were included in the analysis. Median length of follow up was 31 months (range <1-356), and 217/277 (78%) were alive at last follow up. The most common genetic abnormality was FIP1L1::PDGFRA (n=131) followed by D816V KIT mutations (n=39) and alterations involving JAK2 (n=22) (Figure 1). Five patients had genetic abnormalities involving two distinct genes recurrently associated with eosinophilic myeloid neoplasms. The overall median age at diagnosis was 55 years (range 12-89) and 79% of the patients were male. When patients with abnormalities involving PDGFRA and PDGFRB were excluded from the analysis, the male predominance was significantly lower at 62% (p<0.001, Fisher's exact test as compared to the data set as a whole). The overall pattern of organ system involvement was similar irrespective of the underlying genetic abnormality with a few notable exceptions. Cardiac involvement was most common in patients with FIP1L1:: PDGFRA, abnormalities involving JAK2 or without pathologic alterations identified (reported in 22%, 32% and 30%, respectively); whereas skin and gastrointestinal involvement, lymphadenopathy and splenomegaly were most frequent in patients with KIT D816V. Laboratory abnormalities also differed between groups. Whereas anemia was the most common blood abnormality (reported in >50% of patients), erythrocytosis was noted primarily in patients with abnormalities involving JAK2. In contrast, circulating blasts were identified in 70% of patient with BCR::ABL1 and 29% of patients with chromosomal abnormalities or KIT D816V, but in <15% of patients in any of the other groups. Whereas peak AEC alone did not discriminate between the different patient groups, the AEC/tryptase ratio was increased in patients with PDGFRA-associated myeloid neoplasms, molecular abnormalities involving JAK2, or chromosomal abnormalities as compared to those with KIT mutations (Figure 2). Conclusions. Despite the limitations of retrospective data analysis, the data from this large multicenter cohort of patients with HES due to a chronic myeloid neoplasm suggest that routine demographic, clinical and laboratory features vary depending on the underlying molecular abnormality. This approach could ultimately help guide empiric therapy when molecular studies are negative or unavailable.