Mangan, James K.

Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (<0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

Abstract Background: Older adults with newly diagnosed ALL treated with conventional chemotherapy have poor survival due to high rates of toxic death and disease relapse. The Alliance A041703 trial (NCT0373981) tested chemotherapy-free treatment with the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin (InO) followed by the anti-CD19-CD3 bifunctional T-cell engager blinatumomab (blina) without maintenance in older adults to reduce toxicity and increase efficacy of therapy for this patient (pt) population. We previously reported with 22-month (mo) median follow-up that the study met its primary endpoint with a 1-year (yr) event-free survival (EFS) of 75% (90% confidence interval [CI] 63-89% lower bound exceeding null rate of 10%; JCO 2023 41, 7006). Here we report secondary outcomes with 45-mo median follow-up: 3-yr EFS, 3-yr overall survival (OS), response, and relapse characteristics. Methods: Eligible pts were ≥60 yrs old with newly diagnosed, Ph-negative, CD22-positive (≥20% of blasts) B-cell ALL without planned allogeneic HCT (alloHCT), liver disease, or CNS involvement at enrollment. Induction IA was InO 0.8 mg/m2 day (d) 1, 0.5 mg/m2 d8, d15 IV on a 21d cycle. Pts with adequate cytoreduction (marrow blasts reduced ≥50% or marrow cellularity ≤20%) after IA went to IB if in CR/CRi (InO 0.5 mg/m2 d1, d8, d15 IV; 28d cycle) or IC if no CR/CRi (InO 0.8 mg/m2 on d1 and 0.5 mg/m2 on d8 and d15 IV; 28d cycle). Those without cytoreduction to IA started course II blina. Pts without events in IA/B/C received course II blina continuous IV (9 mcg/d x 7d then 28 mcg/d x 21d; 14d break; 28 mcg/d x28d). Pts with CR/CRi to InO received 2 more 28d cycles of blina; others received 3 more. CNS prophylaxis was methotrexate 15 mg intrathecal x 8 doses. EFS was time from therapy start to failure to achieve CR/CRh/CRi by the end of course II, progression, relapse, or death, whichever occurred first, censored at last follow up. OS was time from registration to death from any cause censored at the last known alive date. Results: The median age of the 33 treated pts was 71 yrs (range 60-84). Eight pts had prior therapy for alternate malignancy in CR for >2 yrs prior to enrollment (6 multiple myeloma, 1 non-Hodgkin lymphoma, 1 breast cancer). Median CD22 expression was 92% (range 21-100%) and 49% had NCCN poor-risk genetics. Five pts underwent alloHCT in first CR/CRi and 2 pts received POMP maintenance after early discontinuation of blina (1 toxicity, 1 physician choice). The CR/CRi rate after InO was 85% (1 early death/refractory, 2 refractory, 2 undetermined due to low marrow cellularity on remission assessment marrow) with CR/CRi rate of 97% by completion of course II blina. With 45 mo median follow-up, the estimated 3-yr EFS was 48% (95% CI 33-70%) with a median EFS of 31 mo (95% CI 17.4-not reached [NR]) and no events after 31 mo. Sixteen events occurred: 12 relapses, 1early death, and 3 deaths in remission (1 encephalopathy, 1 relapse of multiple myeloma, 1 pulmonary complications after alloHCT). No isolated CNS relapse has been reported. Among relapses, 10 had immunophenotyping. Four (40%) were CD19-negative, one of which was also CD22-negative. Among CD19-negative relapses, genetics were hypodiploid (2), Pax5alt (1), and ZNF384-like (1, also CD22-negative). TP53 mutation or loss was observed in 5/12 (42%) relapses. Thirteen pts died. The estimated 3-yr OS was 59% (95% CI 44-79%) with median OS NR (95% CI 32-NR) with no deaths after 36 mo. In univariate analysis, EFS and OS were not impacted by age, gender, genetic risk (NCCN), prior therapy for alternate malignancy, or alloHCT in first remission. EFS was better with higher CD22 expression at diagnosis (≥90% vs <90%, 3-yr EFS 60% vs 25%, P=0.044). EFS and OS were worse for detectable minimal residual disease (MRD) at any timepoint by ASO-PCR. Undetectable MRD after course IA (1 cycle InO induction) was associated with EFS with a 3-yr EFS of 52% vs 0% for detectable MRD (median NR vs 8 mo, hazard ratio [HR] 0.07, P=0.004) and a 3-yr OS of 100% vs 0% for detectable MRD (median NR vs 20 mo, HR 0.00, P=0.0014). Conclusions: Longer follow-up of chemotherapy-free treatment with InO and blina for older pts with newly diagnosed, Ph-negative, CD22-positive, B-cell ALL reveals durable remissions and survival. The A041703 regimen is a compelling option for first-line treatment of this pt population. Support: U10CA180821, U10CA18088; https://acknowledgments.alliancefound.org.

Abstract Introduction: Leukemogenesis is driven by nucleophosmin 1 mutations(NPM1-m) or lysine methyltransferase 2A rearrangements(KMT2A-r) in ~35–40% of acute myeloid leukemia (AML) cases. Nearly half of AML patients will develop relapsed/refractory (R/R) disease within a year, with <20% expected response rate following venetoclax/azacitidine (Ven/Aza) and progressively poorer outcomes with each subsequent line of therapy. Ziftomenib–a potent, highly selective, oral, investigational menin inhibitor–has demonstrated clinical activity as both monotherapy and in combination for adults with R/R NPM1-m or KMT2A-r AML. KOMET-007 (NCT05735184) is an ongoing, open-label, ph1a/b study of ziftomenib in combination with standard chemotherapies in adults with newly diagnosed and R/R NPM1-m or KMT2A-r AML. Here we present updated safety and clinical activity in patients with R/R AML treated with the recommended ph2 dose (RP2D) of ziftomenib 600 mg in combination with Ven/Aza across ph1a/b. Methods: Adults (≥18y) with R/R NPM1-m or KMT2A-r AML enrolled independently into separate arms; patients in dose escalation (ph1a) and expansion (ph1b) were treated with oral ziftomenib 600 mg once daily (QD; continuously from C1D8 onward) plus standard doses of Ven/Aza. Primary endpoints: AEs, complete remission (CR; ELN 2022), dose limiting toxicities (DLT; ph1a only). Key secondary endpoints: composite CR (CRc; CR with full, partial or incomplete hematologic recovery), overall response, duration of response. Results: As of June 25, 2025, 80 patients (51 NPM1-m, 29 KMT2A-r) with R/R AML were enrolled (20 ph1a; 60 ph1b) and treated with ziftomenib 600 mg QD + Ven/Aza. Median age was 63y (range 19–85), 50% were female, 74% had ECOG PS 0–1; 22 (28%) had FLT3 co-mutations and 7 (9%) had IDH co-mutations. Median number of prior therapies was 1 (range 1–6); 18% (14/80) had prior stem cell transplant; 25 (49%) NPM1-m and 19 (66%) KMT2A-r patients had prior Ven exposure. 71 patients (89%) had Gr ≥3 treatment-emergent AEs, most commonly (≥20% of patients) febrile neutropenia (31%), decreased platelet count (28%), decreased white blood cell count (26%) and decreased neutrophil count (23%). Gr ≥3 ziftomenib-related AEs occurred in 30 patients (38%), most commonly febrile neutropenia (9%) and anemia (8%). 6% of patients discontinued ziftomenib treatment due to AEs. Differentiation syndrome (DS) occurred in 1 (1%) NPM1-m patient (Gr 3), which lasted 1d and successfully resolved with protocol-specified DS mitigation. No ziftomenib-related QTc prolongation was reported with the combination, and no DLTs were observed in ph1a. 70 patients (43 NPM1-m; 27 KMT2A-r) were response-evaluable (≥1 response assessment or death). Median follow-up was 18.0 wks for NPM1-m and 16.4 wks for KMT2A-r. Overall response rates (ORRs) were 65% (28/43) for NPM1-m and 33% (9/27) for KMT2A-r. CRc rates were 49% (21/43) for NPM1-m and 22% (6/27) for KMT2A-r after median time to first CRc of 4.9 wks (range 2.7–15.6) and 5.5 wks (range 2.6–18.9), respectively; measurable residual disease (MRD)-negativity rates (local) among tested CRc responders were 50% (9/18) for NPM1-m and 60% (3/5) for KMT2A-r after median time to first MRD-negativity of 5.9 wks (range 2.9–15.6) and 8.1 wks (range 7.7–18.9), respectively. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 43d overall (43d for NPM1-m; 71d for KMT2A-r), and median time to platelet recovery (≥100×109/L) was 27d overall (27d for NPM1-m; 23d for KMT2A-r). As of the data cutoff, overall median duration of CRc was not estimable; median overall survival was not estimable for NPM1-m and 21.1 wks for KMT2A-r. In Ven-naive patients, CRc rates were 71% (15/21) for NPM1-m and 33% (3/9) for KMT2A-r; CR rates were 48% (10/21) and 11% (1/9); and ORRs were 81% (17/21) and 56% (5/9), respectively. The study is ongoing with 44% (19/43) of NPM1-m and 11% (3/27) of KMT2A-r patients still on treatment, with responses continuing to evolve.Updated data to be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg QD + Ven/Aza was well tolerated with robust clinical activity in patients with R/R NPM1-mor KMT2A-rAML. No ziftomenib-related QTc prolongation was reported. One case of DS (NPM1-m, Gr 3) successfully resolved with protocol-specified mitigation. These data support further investigation of ziftomenib-based combinations in R/R NPM1-mand KMT2A-rAML.

PURPOSE Older patients with ALL receiving conventional chemotherapy have poor survival due to toxic death and relapse. We hypothesized that a chemotherapy-free, targeted regimen using the anti-CD22 antibody-calicheamicin conjugate inotuzumab ozogamicin followed by the bispecific anti-CD19/CD3 T-cell engager blinatumomab would reduce toxic death and yield high rates of prolonged remission and survival. METHODS Eligible patients were age 60 years and older with untreated, Philadelphia chromosome (Ph)–negative, CD22-positive, B-cell ALL. Patients received up to two cycles of inotuzumab ozogamicin followed by four or five cycles of blinatumomab with intrathecal methotrexate CNS prophylaxis. The primary end point was 1-year event-free survival (EFS). RESULTS The 33 eligible patients had a median age of 71 years (range, 60-84) and a median CD22 expression of 92% (range, 21%-100%). Eight (24%) had previous chemotherapy or radiation for other cancers, six for multiple myeloma. The composite complete remission rate was 85% after two cycles of inotuzumab ozogamicin and 97% by the end of two cycles of blinatumomab. At a median follow-up of 30 months, the 1-year EFS and overall survival were 75% (95% CI, 61 to 92) and 85% (95% CI, 73 to 98), respectively. EFS was shorter with lower CD22 expression or detectable measurable residual disease at any time point. CONCLUSION Inotuzumab ozogamicin then blinatumomab without maintenance chemotherapy in older patients with untreated, Ph-negative, CD22-positive, B-cell ALL yields a high remission rate and excellent EFS. Given the lack of standard, safe, and effective therapies in this population, the regimen should be considered a standard treatment option.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

Background: Chimeric antigen receptor (CAR) T cells have repeatedly demonstrated capacity to induce high rates of response and durable remissions for B cell cancers. In contrast, CAR T cells for the treatment of acute myeloid leukemia (AML) have not yet achieved this impact. We previously demonstrated that CD123 is expressed on AML blasts at high frequency, thus making it an attractive target antigen for AML-directed CAR T cells. Methods and Results: We conducted a pilot study of CD123-directed CAR T cells (CART-123) in adults with relapsed or refractory AML. The primary objective was safety with a secondary objective of anti-leukemia efficacy. Twenty-two subjects were screened, and 20 were eligible for the trial. Fludarabine and cyclophosphamide were used for lymphodepletion (LD). Twelve subjects were infused with CART-123. There were two treatment-related deaths due to cytokine release syndrome (CRS) and infection. Four subjects (33%) achieved complete response with incomplete count recovery (CRi), three subjects had progressive disease, and five had stable disease. Of the four who achieved CRi, one subject remains alive in remission after a relapse and subsequent consolidative hematopoietic stem cell transplant (HSCT). One other subject is alive after HSCT following CART-123 failure. There was evidence of CAR T cell expansion and ten subjects (83%) experienced clinical CRS ranging from Grade I to Grade V. There was no neurotoxicity. To address the apparent paradox of high rates of CART-123 bioactivity (clinical CRS and in vivo expansion) co-occurring with low rates of response, we hypothesized that cytokines produced during CRS may undermine the anti-AML effect of CART cells. We obtained serum drawn from trial subjects at baseline (prior to LD chemotherapy) or during CRS. Serum drawn during CRS promotes primary AML survival in cell culture, while matched baseline serum from the same subjects does not. Individual cytokines secreted during CRS that signal through receptors expressed on myeloid progenitors (such as GM-CSF and Flt3 ligand) reproduced this survival advantage in primary AML blasts when tested at physiologically relevant levels. In contrast, these cytokines did not produce a pro-survival effect in primary patient B-ALL blasts. Crucially, candidate myeloid-acting cytokines, as well as serum drawn during the peak of clinical CRS, promoted resistance of AML to killing by CART-123 in vitro. Using scRNAseq of bone marrow aspirates from subjects on this clinical trial, we found that GM-CSF and FLT3L were most frequently expressed by CD4+ T cells. Exposure of primary AML samples to CRS cytokines led to upregulation of signaling (e.g. JAK/STAT5) and pro-survival pathways. In previous work in B-ALL, we showed that relative resistance to killing can translate to a functional deficit in CART-19 due to development of exhaustion in the CART cells. We similarly find that that exposure to GM-CSF reduces AML blast sensitivity to CART-123, and that the persistence of antigen leads to exhaustion in CART cells (Figure 1). Specifically, co-incubation of CART-123 cells and cytokine-exposed primary AML blasts leads to increased populations of PD-1+/CD39+/CTLA4+/LAG3+ CAR T cells, consistent with an exhaustion phenotype. Finally, we found that anti-apoptotic effects of cytokines can be prevented, and CART-123 killing of AML can be restored, via ruxolitinib blockade of JAK/STAT signaling in both in vitro and in vivo settings. Significance: Our work reveals CRS as active in undermining CART-123 lethality first by promoting survival of AML, and subsequently by exhausting CAR T cells. This is in stark contrast to its role in lymphoid malignancies and underscores biological differences in myeloid versus lymphoid neoplasms. These results highlight a need to tailor therapy to limit cytokine effects on AML blasts to improve outcomes with AML-directed CAR T cell therapy.

7006 Background: Older adult patients (pts) with Philadelphia-chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) have poor survival with chemotherapy. The α-CD22 Ab-drug conjugate inotuzumab ozogamicin (InO) and α-CD19/CD3 T-cell engager blinatumomab (blina) were each superior to chemotherapy in Phase III studies in relapsed/refractory B-ALL. Because InO induces high CR rates and blina can induce durable remissions in low burden disease, we conducted a Phase II trial of induction InO then blina for older adults with newly-diagnosed (ND), Ph-, B-ALL. Methods: Eligible were pts ≥60 years old with ND, Ph-, CD22+ (≥20% of blasts) B-ALL without plan for allogeneic HCT (alloHCT). Pts with CNS leukemia or liver disease were excluded. Induction IA was InO 0.8 mg/m 2 day (d) 1, 0.5 mg/m 2 d8, d15 IV on a 21d cycle. Pts with adequate cytoreduction (marrow blasts by ≥50% or cellularity ≤20%) after IA went to IB if in CR/CRi (InO 0.5 mg/m 2 d1, d8, d15 IV; 28d cycle) or IC if no CR/CRi (InO 0.8 mg/m 2 on d1 and 0.5 mg/m 2 on d8 and d15 IV; 28d cycle). Those without cytoreduction to IA started course II blina. Pts without events in IA/B/C received course II blina CIV (9 mcg/d x 7d then 28 mcg/d x 21d; 14d break; 28 mcg/d x28d). Pts with CR/CRi to InO received 2 more 28d cycles of blina, others received 3 more. CNS prophylaxis was methotrexate 15 mg intrathecal x 8. The primary endpoint was 1-yr event-free survival (EFS) with a lower limit of a 90% CI for 1-yr EFS >10% defined as success. EFS was the time from therapy start to failure to achieve CR/CRh/CRi by end Course II, progression, relapse, or death, whichever occurred first. Results: Thirty-three eligible pts were treated (1 ineligible, 2 nd malignancy). The median age was 71 years (range 60-84). Median WBC count was 3,200/mcl (range 6-38,000). Median CD22 expression was 92% (range 21-100%). Eight pts had therapy-related ALL. The cumulative CR rates through Course IA/B/C and Course II were 85% and 97%, respectively (Table). With median follow up of 22 mo, the 1-yr EFS was 75% (95% CI 61-92%). The 2-sided 90% CI was 63-89% for 1-yr EFS with lower bound above 10% indicating regimen success. Twelve pts had events: 9 relapses, 2 deaths in remission (1 after alloHCT), and 1 death without remission from respiratory failure with sinusoidal occlusion syndrome of liver. The 1-yr OS was 84% (95% CI 72-98%). Nine pts have died, 6 after relapse. Conclusions: InO induction then blina consolidation is highly active for ND, Ph-, CD22+ B-ALL. The regimen is an option for older adults and a comparator regimen for future studies. Support: U10CA180821, U10CA180882, U10CA180820 https://acknowledgments.alliancefound.org . Clinical trial information: NCT03739814 . N=33 I A/B/C II Composite CR* 28 ( 85%) 32 ( 97%) CR 15 (45%) 19 (58%) CRh 11 (33%) 12 (36%) CRi 2 (6%) 1 (3%) Refractory 3 (9%) † - 1-yr EFS 75% (95% CI 61-92%) 1-yr OS 84% (95% CI 72-92%) *CR+CRh+CRi † 1 completed IA only

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.