Burke, Patrick W.

Abstract Introduction: While newly diagnosed patients (pts) with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy have prolonged survival outcomes with venetoclax plus azacitidine (VEN+AZA) over AZA alone (2-year overall survival rate: 37.5% vs 16.9%), more can be done to further enhance outcomes (Pratz et al., 2024). CD123 is overexpressed on AML blasts and leukemia stem cells in AML. Pivekimab sunirine (PVEK) is a first-in-class antibody-drug conjugate comprised of a high-affinity anti-CD123 antibody, a cleavable linker, and an indolinobenzodiazepine pseudodimer payload. Previously, in pts with CD123-positive AML, PVEK combined with VEN+AZA demonstrated robust response rates with a manageable safety profile (Daver et al., 2023). Here we report a subgroup analysis from a preliminary cohort of frontline (1L)-treated pts with AML. Methods: Data are from the dose expansion phase of an ongoing, open-label, multicenter, fully enrolled, Phase 1b/2 study of PVEK+VEN+AZA in adults with 1L unfit AML deemed CD123-positive by investigator. Unfit pts were aged ≥75 years (yr), or aged <75 yr with Eastern Cooperative Oncology Group performance status (ECOG PS) score 2–3, or ≥1 defined comorbidity. Pts received PVEK (0.045 mg/kg, intravenous [IV]) on Day (D) 7 plus VEN (400 mg equivalent, oral) daily in a 28-D cycle (cohort 1 received ≥14 D of VEN; cohort 2 received 28 D of VEN) plus AZA (up to 75 mg/m2, subcutaneous or IV) on D1–7. Bone marrow assessments were performed by D12–14 (cohort 1) or D18–21 (cohort 2) to determine VEN duration in cycle 1 and at the end of every subsequent cycle to assess responses and myelosuppression. The primary endpoint was antileukemia activity (complete remission [CR] rate) and measurable residual disease (MRD) assessments. Responses were determined using the modified European LeukemiaNet 2017 criteria (plus CR + partial hematologic recovery [CRh]). MRD-negativity was defined centrally as <0.1% using multiparameter flow cytometry. Safety was assessed as a secondary endpoint. Results: Among 1L unfit pts with CD123-positive AML (n=49), the median (range) age was 77 (58–85) yr, with most pts aged ≥75 yr (n=36 [74%]). Forty-two (86%) pts reported an ECOG PS ≤1, 14% (n=7) had secondary AML, and 20% (n=10) and 51% (n=25) had intermediate or adverse cytogenetic risk, respectively; 65% (n=32) and 35% (n=17) were reported as TP53wt or TP53mut, respectively. Eight (16%) pts bridged to stem cell transplant. The median (range) number of treatment cycles and duration of treatment were 4 (1–20) and 5.5 (0.7–22.7) months (mo), respectively, for PVEK; 4 (1–20) and 5.1 (0.9–22.9) mo for VEN; and 4 (1–21) and 5.7 (0.9–23.4) mo for AZA. For cohort 1 (n=10), the median (range) duration of VEN was 4.5 (2.1–22.9) mo, and for cohort 2 (n=39), the median (range) duration of VEN was 5.7 (0.9–15.2) mo. With a median (range) follow-up of 10 (1.2–26.7) mo, 63.3% (95% CI: 48.3%–76.6%) of pts achieved CR, 79.6% (95% CI: 65.7%–89.8%) achieved CR/CR with incomplete hematologic recovery (CRi), and 73.5% (95% CI: 58.9%–85.1%) achieved CR/CRh; morphologic leukemia free state was achieved in 4% (n=2) of pts. Of pts who achieved CR or CR/CRi with a MRD-evaluable sample, 92% (23/25) and 90% (27/30) achieved flow cytometry MRD-negativity (<0.1%) respectively. The most common (≥50% of pts) any grade treatment-emergent adverse events (AEs) were neutropenia/neutrophil count decreased and thrombocytopenia/platelet count decreased (both 69%); constipation (61%); and peripheral edema (51%). Three pts (6%) experienced AEs leading to discontinuation (myocardial infarction/soft tissue infection/thrombocytopenia) and 2 pts had AEs leading to death (respiratory failure/pancytopenia). Conclusions: Unfit pts with newly diagnosed CD123-postive AML demonstrated high CR rates with PVEK+VEN+AZA. These robust response rates were observed across the select mutational profiles tested. Follow up with duration of response and survival estimates among all pts, by molecular subgroups and MRD negativity status, are being evaluated. Triplet therapy in unfit 1L pts with CD-123–positive AML was well-tolerated, and no new safety signals were observed. These data highlight the need to further evaluate this regimen in a randomized trial.

Background: Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a heterogenous subtype of B-ALL defined by the presence of gene expression profiling similar to Ph+ ALL in the absence of a BCR::ABL1 fusion. Ph-like ALL has lower response rates to standard frontline therapies and carries a poorer prognosis when compared to other B-ALL subtypes. However, the role in which specific patient characteristics may impact responses is not well described. Our aim for this retrospective study was to evaluate the characteristics and outcomes of a real-world cohort of patients (pts) with Ph-like ALL across multiple institutions, including describing key patient characteristics, treatments, and factors that may contribute to minimal residual disease (MRD) status and treatment response. Methods: We conducted a retrospective review of adult pts with Ph-like ALL diagnosed and treated at the University of New Mexico, Mayo Clinic Phoenix, University of Chicago, and University of Michigan between 1/1/18 - 2/1/2024. Pts were eligible if they carried a diagnosis of B-ALL, and were determined to have Ph-like ALL according to each institutional diagnostic algorithm. Descriptive statistics, ANOVA, and Fisher's exact test were employed to summarize various clinical characteristics and their associations. Cox regression analysis was utilized to estimate the median survival time and assess the relationship between clinical characteristics and survival outcomes, including overall survival and progression-free survival. All statistical analyses were conducted using the R statistical software. Results: 67 pts were identified with a median age of 34.2 (IQR 28.5) and 35.8% were female. Twenty-eight pts identified as Hispanic or Latino (H/L) (43.1%), 25 (38.5%) identified as non-Hispanic White/Caucasian (NHW), 10 (15.4%) as American Indian/Alaska Native (AI/AN), and 2 (3.1%) as Asian/Pacific Islander. Thirteen pts (19.4%) had central nervous system (CNS) involvement at diagnosis, 22.4% of pts had extramedullary disease, and, in those who had NGS or cytogenomic microarray testing (n=49), 51% had an identified mutation/deletion in IKZF1. Initial treatment varied widely with pts receiving most commonly: Children's Oncology Group (COG) protocols (22.4%), CALGB 10403 (22.4%), HyperCVAD (11.9%), and CALGB 8811 (10.4%). Fifty-eight percent achieved a CR/CRi and 21% were refractory to initial therapy. Thirteen percent of pts received a Jak inhibitor and 6% of pts were treated with a TKI. Thirty pts (50.8%) underwent allogeneic stem cell transplant, with 8 of those pts (26.7%) experiencing a relapse post-transplant. Nine pts (13.4%) underwent treatment with CAR-T therapy with few pts experiencing grade 2 or higher cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Pts with CNS disease at diagnosis were less likely to achieve a CR/CRi compared to those without CNS disease at diagnosis (33.3% vs 64.0%; p=0.12). Pts identifying as AI/AN were more likely to be refractory to their first treatment compared to other racial/ethnic groups (75%, p=0.002). Forty two percent of pts never achieved MRD negativity (< 0.01% by flow cytometry) during treatment; pts identifying as H/L and AI/AN had a higher rate of MRD positivity after induction compared to NHW pts (56% and 70% vs. 25%; p=0.02). In pts with IKZF1 mutation, 57.1% did not achieve MRD negativity compared to 21.7% in pts without a mutation (p=0.029). The median overall survival (OS) was 66.3 months (mos) and the median progression-free survival (PFS) was 15.7 mos. Pts who did not achieve MRD negativity after initial treatment had shorter OS compared to those who did achieve MRD negativity, 33.9 mos vs 66.3 mos (p=0.086). Progression-free survival (PFS) was significantly shorter for patients who did not achieve MRD negativity after initial treatment compared to those who did, 3.9 mos vs 43.9 mos (p=0.001). PFS was shorter in pts who identify as AI/AN compared to H/L and NHW pts (2 mos vs 35.7 mos and 35.7 mos; p=0.046). Conclusion: Pts with Ph-like ALL experience poor response rates to therapies used to treat B-ALL, highlighting the urgent need for novel therapies and treatment strategies. We identified race/ethnicity and CNS disease at diagnosis as risk factors for poor treatment response. In addition, race/ethnicity and the presence of an IKZF1 mutation was associated with worse rates of MRD negativity during treatment.

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.

TPS6585 Background: Despite improved outcomes with azacitidine (AZA) and venetoclax (VEN) in newly diagnosed (ND) unfit acute myeloid leukemia (AML), only a subset of patients (pts) respond (CR 37%; CR/CRi 66%) and long-term survival remains inadequate (mOS <15m, DiNardo NEJM 2020). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). CD123 is expressed on the majority of AML blasts and leukemic stem cells while minimally expressed on normal hematopoietic stem cells (Kovtun Blood Adv 2018). Pivekimab sunirine (PVEK, IMGN632) is an antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The IGN payload alkylates DNA and causes single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. Clinical data from the first 50 pts in the dose expansion cohorts 1 and 2 with ND AML demonstrated a 76% (22/29) MRD negativity rate (by flow cytometry, negativity threshold <0.1%) (Daver ASH 2023), supporting the continued enrollment of the PVEK+AZA+VEN triplet and further evaluation of the regimen’s antileukemia activity and safety in consideration of potential registration-enabling trials. Methods: This is an open-label, multicenter, phase 1b/2 study of PVEK administered in a combination with AZA+VEN in pts with ND CD123-positive (CD123+ by flow cytometry or IHC) AML, with no prior treatment with hypomethylating agents (HMA). Pts will receive the recommended phase 2 dose of PVEK 0.045 mg/kg IV as a < 30-minute outpatient infusion on day 7, AZA 75 mg/m2 SC or IV daily on days 1 to 7, and VEN 400 mg PO daily for up to 28 days in a 28-day cycle. During cycle 1, a bone marrow evaluation at or around day 21 is required to inform VEN dose duration. Current eligibility criteria for continued enrollment of AML patients unfit for intensive chemotherapy include age ≥ 75 years old, or age < 75 years old with ECOG 2-3, or at least one defined comorbidity. The primary study objectives are to assess antileukemia clinical activity (composite CR [complete remission] rate, overall response rate, duration of remission) and MRD-negativity rates. Key secondary objectives are safety and tolerability, pharmacokinetics and immunogenicity. The PVEK+AZA+VEN triplet in pts with ND unfit AML is currently enrolling across sites in France, Germany, Italy, Spain, UK and USA. Clinical trial information: NCT04086264 .

Background In unfit patients (pts) with newly diagnosed (ND) AML, long-term survival remains short (mOS 14.7 months) despite improved responses (CR 37% and CR/CRi 66%) with azacitidine (AZA) and venetoclax (VEN) (VIALE-A, DiNardo NEJM 2020). In a pooled analysis of AZA-VEN in ND AML pts with poor risk cytogenetics the response rates were higher in TP53wt pts (CR/CRi 70%) compared with TP53mut pts (CR/CRi 41%) (Pollyea Clin Cancer Res 2022). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). Pivekimab sunirine (PVEK, IMGN632) is a first-in-class antibody-drug conjugate (ADC) comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The novel IGN payload alkylates DNA and causes single strand breaks without crosslinking (Kovtun Blood Adv 2018). Methods This is an ongoing, open-label, multicenter, Phase 1b/2 study of PVEK in combination with AZA +VEN in adults with ND CD123-positive AML (any CD123+ expression by local flow cytometry or IHC). Pts received the recommended phase 2 dose of PVEK 0.045 mg/kg IV on D7 + AZA 75 mg/m 2 SC or IV daily on D1-7 + VEN up to 400 mg PO daily for 14 to 28 days (based on cohort assignment) in a 28-day cycle. Bone marrow assessment was performed at D14 (cohort 1) or D21 (cohort 2) of cycle 1 to determine VEN duration. The primary endpoints are composite CR rate (CCR [CR+CRh+CRp+CRi]), MRD rate (assessed centrally [Hematologics, Inc.] by flow cytometry; &lt;0.1% defined as negative) and duration of remission. Key secondary endpoints are safety, pharmacokinetics and immunogenicity. Responses were determined using ELN 2017 criteria (with the addition of CRh) and a 14-day post-marrow count recovery window. Results As of July 17, 2023, data is available for 50 ND pts (n=25 per cohort) treated with PVEK+AZA+VEN and are aggregately reported here. The median age was 74 years (range, 46-83), 42% were ≥ 75 years old, 26% had secondary AML, 64% were ELN 2017 adverse risk, and 38% had a TP53mut. The most common non-hematologic treatment-emergent adverse events (TEAE) (all grades [grade 3+]) seen in &gt; 20% of all pts were febrile neutropenia (44% [38%]), constipation (42% [2%]), peripheral edema (36% [4%]), diarrhea (36% [2%]), hypophosphatemia (32% [0%], nausea (28% [4%]), and hypokalemia (24% [2%]). No veno-occlusive disease (VOD) events were reported. In responders, the median time to achieve absolute neutrophil count ≥500/µL and platelet count ≥50,000/µL was 35.5 days (range, 20-55) and 22 days (range, 20-55), respectively. The median post-remission cycle delay (beyond cycle day 28) was 14 days. Two pts discontinued PVEK due to a TEAE (edema; marrow aplasia). The 60-day mortality was 4%. In the ITT population (N=50) the CR rate was 52% (26/50), and the CCR rate was 66% (33/50). In pts ≥ 75 years old, the CCR rate was 76% (16/21). In pts known to be TP53wt, both the CR and CCR rate was 88% (22/25). Additional response subsets in Table 1. Twenty-one pts received 9-14 days of VEN, 9 pts received 15-21 days of VEN and 20 pts received ≥ 22 days of VEN in cycle 1; of those who received ≤ 14 days of VEN the CR rate was 71% (15/21) and the CCR rate was 76% (16/21). Of the 26 pts who achieved CCR and had an MRD-evaluable sample, 73% (19/26) achieved MRD negativity (CCR MRD-, &lt;0.1% residual blasts); notably all had undetectable MRD levels (lower level of detection is 0.02%). MRD-negativity was achieved rapidly with a median of 1.7 months (range, 0.8-4.5). CCR MRD- rates were high across major molecular subsets, including FLT3 (ITD/TKD) at 100% (7/7), IDH1/2 at 89% (8/9), and NPM1 at 89% (8/9), as well as ELN risk groups (intermediate 80% [8/10]; adverse 64% [9/14]). Conclusion With a manageable safety profile in pts with ND AML, the PVEK+AZA+VEN triplet demonstrated anti-leukemia activity with robust CR rates and early MRD negative responses in a cohort enriched for adverse disease characteristics (64% ELN adverse risk; 38% TP53mut). Encouraging CCR MRD- rates were observed across cytogenetic/molecular subsets, and the majority of responding pts achieved early and deep remissions, which may translate to improved clinical outcomes. The regimen was well tolerated with no new safety signals, and the addition of PVEK to the AZA-VEN backbone did not appear to meaningfully prolong count recovery.

TPS7073 Background: Despite improved outcomes with azacitidine (AZA) and venetoclax (VEN) in frontline unfit AML (CR 37% and CR/CRi 66%), long-term survival for these patients remains inadequate (mOS < 15m, DiNardo NEJM 2020). CD123 is expressed on the majority of AML blasts and leukemic stem cells while minimally expressed on normal hematopoietic stem cells (Kovtun Blood Adv 2018). Pivekimab sunirine (PVEK, IMGN632) is an antibody-drug conjugate (ADC) comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The IGN payload alkylates DNA and causes single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. Clinical data in relapsed/refractory (R/R) AML (Daver ASH 2022) supported the continued clinical exploration of the PVEK+AZA+VEN triplet. The current enrolling dose expansion cohorts (Regimen C; Cohorts 1 and 2) in frontline AML will evaluate antileukemia activity and MRD levels in the combination of PVEK+AZA+VEN. Regimen E will enroll patients with R/R AML to evaluate the safety and antileukemia activity of PVEK in combination with magrolimab. Methods: This is an open-label, multicenter, Phase 1b/2 study of PVEK administered in combination regimens in patients with frontline and R/R CD123-positive AML. Patients will receive the established recommended phase 2 dose (RP2D) of PVEK 0.045 mg/kg IV, as a < 30-minute outpatient infusion. In Regimen C, patients will receive PVEK 0.045 mg/kg IV on D7 + azacitidine 75 mg/m 2 SC or IV daily on days 1 to 7, and venetoclax up to 400 mg PO daily for at least 14 days (Cohort 1) or for up to 28 days (Cohort 2) in a 28-day cycle. In Regimen E, R/R AML patients will receive PVEK 0.045 mg/kg IV on D1 of the 28-day cycle in combination with magrolimab at 30 mg/kg Q2W, after the standard ramp up schedule. Regimen C will enroll adults with untreated AML, CD123+ by flow cytometry or IHC and no prior HMA treatments. The primary endpoints for Regimen C are composite CR rate, overall response rate (ORR), duration of remission (DOR), MRD levels and key secondary endpoints are safety, PK and immunogenicity. Regimen E will enroll adult patients with relapsed or refractory CD123+ AML with up to 2 prior lines of therapy. The primary endpoint for Regimen E is dose limiting toxicities (DLTs) and key secondary endpoints are safety, antileukemic activity, PK and immunogenicity. The PVEK+AZA+VEN triplet (Regimen C) is currently enrolling frontline unfit patients across sites in France, Germany, Italy, Spain, UK and USA. The PVEK+Magro doublet (Regimen E) is planned to be open for enrollment mid-2023 at sites in the USA. Clinical trial information: NCT04086264 .

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) 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. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.