Acute erythroid leukemia treatment is associated with poor survival. The most common treatments are intensive chemotherapy regimens and hypomethylating agents. Choice of preferred therapy is complex, and data are conflicting on the optimal regimen. The definition of AEL has also shifted with time but the impacts of these changes on survival reporting are largely unknown.We designed a single-center, retrospective review of patients meeting the 2001 World Health Organization definition of acute erythroid leukemia. Patients were treated with an intensive chemotherapy or a hypomethylating agent regimen. The primary outcome was overall survival.Most patients were older with complex karyotypes. Median overall survival did not differ between treatment groups. When survival was stratified by WHO 2022 diagnosis, patients meeting MDS criteria had notably increased survival outcomes while patients still meeting the definition of AEL did poorly regardless of induction regimen.Treatment of acute erythroid leukemia remains complex with poor survival outcomes.

Asparaginase (ASNase)-based chemotherapy regimens significantly improve survival outcomes in children, adolescents and young adults (AYA), and even adults with acute lymphoblastic leukemia/lymphoma (ALL); however, the incidence and severity of ASNase-associated adverse events (AE) in adults may differ significantly from those reported in children. Strategies to mitigate, monitor for, and manage toxicities that allow adult ALL patients to receive full ASNase courses are needed. A representative 12-member panel of experts who treat AYA and adult ALL patients, incorporate ASNase into their treatment regimens, and conduct related research was assembled to consider opportunities to optimize the use of pediatric-inspired ALL regimens in these adult patients. Following 2 systematic biomedical literature searches from April 2009 through April 2024, a modified Delphi method was used to distill expert opinion into clinical statements that met a standardized definition of consensus. After 2 iterative Delphi method surveys, 23 statements met the standardized definition of consensus, whereas 19 statements did not. Five statements were merged to avoid redundancy. The clinical statements were grouped into 5 distinct categories: 1) hepatotoxicity; 2) hypersensitivity reactions; 3) thromboembolic and coagulopathy complications; 4) pancreatitis and metabolic complications; and 5) dosing. The intent of these statements is to provide health care providers with information that will help them mitigate, monitor for, and manage the most common and/or unique ASNase-induced AE in adult ALL patients, allowing these patients to receive more or all the planned ASNase doses and thereby improve outcomes.

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.

Venetoclax with hypomethylating agents (HMAs) is an important treatment for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. However, there is limited data on the safety of venetoclax without a dose ramp-up in patients with AML. A retrospective cohort analysis of patients with AML treated with HMA/venetoclax (HMA/Ven) with or without a dose ramp-up, or HMA alone from 6/30/2014-8/22/2022 was conducted. The primary endpoint was the incidence of laboratory and/or clinical tumor lysis syndrome (TLS) by day 10. Of 225 patients, 111 patients received HMA alone or HMA/Ven with a dose ramp-up and 114 received HMA/Ven with no dose ramp-up. The incidence of TLS was similar between the control and no dose ramp-up groups, with rates of 5.4% and 5.3% respectively (p = 0.962). TLS incidence was comparable in patients with and without a dose ramp-up, suggesting that a dose ramp-up may not be mandatory in patients with AML.

Aplastic anemia (AA) is a rare bone marrow failure disorder that is treated with either allogeneic stem cell transplant or immunosuppressive therapy (IST) consisting of antithymocyte globulin (ATG), cyclosporine (CSA), and eltrombopag. While outcomes are favorable in younger patients, older patients (>60) have significantly worse long-term survival. The dose of ATG is often reduced in older patients and those with multiple comorbidities given concerns for tolerability. The efficacy and safety of dose-attenuated IST in this population is largely undescribed. We performed a retrospective review of patients with AA treated with IST. Our analysis was confounded by changes in practice patterns and the introduction of eltrombopag. We identified 53 patients >60 years old, of which, 20 received dose-attenuated IST, with no statistically significant difference in overall survival between full and attenuated dose cohorts. Overall response rates in both cohorts were similar at 6 months at 71% and 68%. There were more documented infectious complications in the full dose cohort (13 vs. 3). This supports the consideration of dose-attenuated IST in older patients with concerns about tolerance of IST. Lastly, our data confirmed favorable outcomes of younger patients receiving IST, especially in combination with eltrombopag.

Background: LP-108 (Lacutoclax) is a potent inhibitor of BCL-2. We explore the toxicity and tolerability of LP-108 as monotherapy and combined with azacitidine (Aza) in patients with relapse/refractory Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML) and high-risk refractory/relapsed Myelodysplastic syndrome (MDS) (EudraCT 2021-001402-29, NCT04139434). Description and aims of the trial: This is a First -in-human (FIH), Phase 1, multicenter, open-label study with dose-escalation of only lacutoclax phase (Phase 1a) and a cohort expansion phase (Phase 1b) combined with Aza. Inclusion criteria were AML, RAEB 1and 2, MDS with IPSS-R>4.5 and CMML with ≥5% of blasts in bone marrow, refractory or relapsed to previous treatment. The primary objective is to characterize safety and tolerability, to define maximum tolerability dose (MTD) recommended phase 2 dose (RP2D) and asses the pharmacokinetics of lacutoclax as monotherapy and combined with Aza. The secondary objective were Overall Response Rate (ORR) the Complete Remission (CR), minimal residual disease (MRD), complete remission with incomplete blood count recovery (CRi), morphologic leukemia free state (MLFS), partial remission (PR), the same in MDS (ORR, CR, PR and marrow CR), progression free survival (PFS), duration of response (DOR), event free survival (EFS) and overall survival (OS). The phase 1 was designed with two arms, monotherapy (Arm 1) and combination therapy with Aza (Arm 2) in a classic 3+3 in order to determine the MTD/OBD and RP2D starting with a dose of 100 mg q d in a 28 daily dosing schedule. Dose Limiting Toxicity (DLT) was described as any extra hematological toxicity ≥3 during the first 28 days of induction or prolonged grade 4 pancytopenia not due to active leukemia beyond 42 days. Adverse events were graded according to the NCI-CTCAE version 5.0. Results: A total of 44 patients (18 Female, 26 Male) were screened. A total of 32 patients were enrolled due to 12 patients deemed screen failures. The median age of the patients was 70 years (40-88 years). The patient population previous diagnosis were AML (20), CMML (4) and MDS (8). The median number of previous lines of therapy were 2 (1-7). Total patients enrolled in the Arm 1 (monotherapy) were 20, and 12 patients were enrolled in Arm 2. Within Arm 1 the dose was increased from 100mg/day (7 patients) to 200 mg/4 patient then to 400 mg/day (4 patients) and finally up to 600 mg/day (3 patients). In Arm 2 (combination therapy) the dose was increase from 100 mg/day (4 patients), 200 mg/day (5 patients) and 400 mg/day (3 patients). No new TAE's of special interest were found. The number serious TAE's >3 were 5 (25%). In Arm 2 100% of the patients experience some type of AE. No TAE's that implies DLT were not seen. The more frequent AE's were gastrointestinal (vomiting 65%), hematological (thrombocytopenia 65%) and increase bilirubin (25%). COVID 19 was only detected in 1 patient. We observed 4 CRc, 1PR and 2MFLS and 2 patients with improvement in its MDS status. Conclusions: Lacutoclax is safe with no apparent extra hematological toxicities and appears as a new anti BCL-2 agent in patients with refractory myeloid malignancies. This agent had encouraging efficacy as both monotherapy and in combination with azacitidine.

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.

Patient education in acute myeloid leukemia (AML) has become increasingly complex with the introduction of new treatments and chemotherapy regimens. Video education presents an opportunity to supplement traditional patient education and address some of the gaps associated with standard methods. This single-center study sought to assess the potential impact of supplemental video education on patients receiving induction chemotherapy for AML. Participants were consented to be randomized to receive their education with or without a supplemental video designed for their treatment regimen. We then provided a survey to each participant to assess knowledge retention, anxiety, and overall satisfaction with their care. Patients that received video education were found to have significantly improved knowledge retention compared to those that did not. There were no differences detected in anxiety or patient satisfaction. Video education appears to be an effective supplemental method for patient education in AML. Limitations include the single-center nature of the study at an urban academic medical center with a relatively well-educated, primarily Caucasian, younger population. Future research is warranted to assess the video in a diverse set of languages and to explore its broader benefits.

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.

Mivavotinib (TAK-659) is an investigational type 1 tyrosine kinase inhibitor with dual activity against spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3). We conducted a phase Ib study to investigate the safety, tolerability, and efficacy of mivavotinib in patients with refractory and/or relapsed (R/R) acute myeloid leukemia (AML). Both daily (QD) and twice daily (BID) dosing regimens were evaluated. A total of 43 patients were enrolled, and there were 5 complete responses (4 with incomplete count recovery). In the QD dosing regimen, the maximum tolerated dose (MTD) was not reached up to 160 mg QD per protocol; 140 mg QD was identified as the recommended phase II dose. In the BID dosing regimen, the MTD was 60 mg BID. Thirty patients (70%) experienced a bleeding event on study; the majority were grades 1 or 2, were resolved without mivavotinib modification, and were not considered related to study treatment. Eleven patients (26%) experienced grade ≥3 bleeding events, which were observed most frequently with the 80 mg BID dose. We conducted platelet aggregation studies to investigate the potential role of mivavotinib-mediated SYK inhibition on platelet function. The bleeding events observed may have been the result of several confounding factors, including AML disease status, associated thrombocytopenia, and high doses of mivavotinib. Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition. ClinicalTrials.gov: NCT02323113.

The incorporation of pediatric-inspired regimens in the adolescent-young-adult (AYA) and adult populations have resulted improved survival outcomes (Stock et al. Blood 133(14):1548-1559 2019; Dunsmore et al. J Clin Oncol 38(28):3282-3293 2020; DeAngelo et al. Leukemia 29(3):526-534 2015). Nonetheless incorporation of such regimens is limited by increased toxicity to asparaginase. Dosing strategies that reduce the weight-based dose of pegylated-L-asparaginase (PEG-asparaginase) utilizing activity monitoring have been shown to result in better tolerability of these regimens. The purpose of this study was to analyze the efficacy and safety of treating adults with Philadelphia chromosome negative (Ph-) ALL with pediatric-inspired regimens that incorporate PEG-asparaginase dose adjustments and asparaginase activity level monitoring. Patients aged 18-65 years initiated on pediatric-inspired regimens utilizing dose-reduced PEG-asparaginase with therapeutic drug monitoring-guided adjustments were included. The screening of 122 patients treated between 2015 and 2021 resulted in the inclusion of 54 patients. The median age of the cohort was 35 years (16-65 years), and median body mass index (BMI) was 30 kg/m2 (18.3-53.4 kg/m2). The 36-month survival estimate was 62.1% (95% CI 48.1-77.7%), and the median overall survival (OS) was 62.2 months (95% CI 35.1-89.3 months). In the AYA cohort, the 36-month survival was 71.2% (95% CI 55.8-91%) and the median overall survival was not reached. Survival was not significantly affected by immunophenotype or BMI. Discontinuation due to toxicity or hypersensitivity reactions was low at 11% and 9% respectively. The encouraging survival outcomes and favorable tolerability of this older population in the real-world setting support the use of individualized PEG-asparaginase dosing with PharmD-guided therapeutic drug monitoring.

This retrospective study was conducted to determine whether the number of peripherally inserted central-catheter lumens affected the rate of central-line associated bloodstream infections (CLABSIs) in adult patients with acute leukemia. The results show that CLABSI rates were not significantly different between patients with triple-lumen or double-lumen PICCs (22.1% vs 23.4%; P = .827).

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; <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 > 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-, <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.

BACKGROUND: Despite recent improvements with azacitidine (AZA) and venetoclax (VEN), long-term survival for these patients remains short (median overall survival 14.7 months) and rationally designed novel additions to this regimen are being evaluated to improve patient outcomes. CD123 is expressed on the majority of AML blasts and leukemic stem cells while minimally expressed on normal hematopoietic stem cells. 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. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. Both preclinical synergy between PVEK and AZA and/or VEN (Kuruvilla ASH 2020) and initial clinical data in R/R AML (Daver ASH 2021) supported the continued clinical exploration of this triplet. Here we report safety and anti-leukemic activity of PVEK+AZA+VEN from the higher-intensity cohorts and ongoing expansion cohort in patients with R/R AML. METHODS: In this phase 1b/2 study, eligible patients with CD123-positive R/R AML received PVEK+AZA+VEN in a three-drug escalation over a 28-day cycle: PVEK 0.015 or 0.045 mg/kg day 7, AZA 50 or 75 mg/m2 days 1-7, and VEN 400 mg (or equivalent with azole) for 8, 14, or 21 days. The higher intensity cohorts are defined as patients treated with PVEK on day 7, and either a PVEK dose at 0.045mg/kg or at least 14 days of VEN. Enrollment of relapsed and frontline patients is ongoing in the expansion cohorts of PVEK 0.045 mg/kg day 7, AZA 75 mg/m2 days 1-7, and VEN 400 mg for at least 14 days. Responses were determined using ELN 2017 criteria (with the addition of CRh and CRp) and a 14-day count recovery window. RESULTS: As of June 20, 2022, preliminary safety data are available for 71 patients with R/R AML treated in the higher-intensity cohorts as defined above. The median age was 68 years (range, 25-82), 30% had secondary AML, 32% had primary refractory disease, 44% had received prior VEN, 25% had prior allogeneic stem cell transplant, and 54% of the patients were ELN 2017 adverse risk. Fifty-two percent of the patients had received ≥ 2 prior lines of therapy. The most common treatment-emergent adverse events (TEAE) (all grades [grade 3+ events]) seen in >20% of patients were febrile neutropenia (30% [24%]) and infusion-related reactions (IRRs, 21% [3%]). Pneumonia was reported in 16% of patients [grade 3+ 11%]. Overall, 10% of patients discontinued PVEK due to a TEAE (mostly unrelated to PVEK). Cytopenias and infections were consistent with those observed with HMA+VEN in patients with R/R AML. 30-day mortality was 3%. Response data were available for 61 patients with R/R AML. The objective response rate (ORR [CR, CRh, CRp, CRi, MLFS) was 51% with a composite complete remission (CCR [CR, CRh, CRp, CRi]) rate of 31%. VEN-naïve patients had an ORR and CCR of 62% and 47% compared with 37% and 11%, respectively, in patients who had prior VEN exposure. Of note, responses were observed in 9 of 11 patients with FLT3-ITD AML with an ORR of 82% and a CCR of 64%. Table 1 displays response data from sub-groups of interest. Additionally, maximum best change in bone marrow blasts is depicted in Figure 1. CONCLUSION: With a manageable safety profile in patients with R/R AML, the higher-intensity cohorts of the novel PVEK triplet demonstrated anti-leukemia activity across several difficult-to-treat subsets of patients. Enrollment and follow-up in both relapsed and frontline patients are ongoing (NCT04086264). Additional and updated safety and efficacy data will be presented at ASH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The PVEK triplet with AZA+VEN demonstrates anti-leukemic activity across multiple high-risk genetic subsets of relapsed/refractory AML. Prophylactic steroids added on day -1 have significantly reduced IRRs. Expansion cohorts are now enrolling for untreated and relapsed AML patients (NCT04086264).

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with a worse prognosis compared to Ph negative ALL. Tyrosine kinase inhibitor (TKI) therapy has led to an improvement in response rates and survival, thus becoming a critical component of therapy. We performed a retrospective cohort study of Ph+ ALL patients treated at the University of Michigan who received TKI therapy pre- and post-allogeneic hematopoietic stem cell transplant (HSCT) from April 2007 to November 2019. The study included 40 patients with Ph+ ALL (47.5% female) with a median age of 54 (24-69) years. Median event-free survival (EFS) was not reached, with a 5-year EFS of 61%. Median overall survival (OS) was not reached, with a 5-year OS of 71%. There was no difference in 2-year EFS or OS for patients on pre-transplant imatinib or dasatinib (p = 0.16, 0.09, respectively), though definitive conclusions are challenging as post-transplant TKI therapy was variable. The incidence of any grade acute graft-versus-host disease (GVHD) was 62.5% (25/40) and any grade chronic GVHD was 77.5% (31/40). Complete molecular remission (CMR) was achieved in 57.5% of patients pre-transplant with no significant difference when stratified by induction TKI (p = 1). Achievement of CMR pre-HSCT showed a trend towards improved 2-year EFS (p=0.0198) but did not significantly change 2-year OS (p = 1). Patients receiving 1st and 2nd generation TKIs pre- and post-HSCT seem to have favorable outcomes, although type of TKI (pre-HSCT) did not significantly impact EFS or OS. In addition, attaining a CMR pre-transplant improved EFS, but did not change OS.

Abstract PEG-asparaginase is a key component in treatment regimens for acute lymphoblastic leukemia (ALL). Major side effects include thrombosis and bleeding; however, there is currently no consensus on methods to prevent these complications. In this multi-center retrospective cohort study of 101 adults, we compared two prophylaxis strategies: cryoprecipitate and fresh frozen plasma (Cryo/FFP) versus cryoprecipitate and antithrombin (ATIII). The overall incidence of venous thromboembolism (VTE) was not significantly different between the two groups (19.7% for Cryo/FFP and 8.6% in Cryo/ATIII, p = 0.17), and neither was grade ≥3 bleeding (3% for Cryo/FFP and 11.4% for Cryo/ATIII, p = 0.18). Given the significant cost associated with ATIII without a clear benefit, a careful benefit and risk analysis should be considered before utilizing ATIII as a prophylaxis strategy to prevent thrombosis or bleeding following asparaginase administration.

BACKGROUND: Despite improvements in the treatment of "unfit or older" AML patients with the combination of azacitidine (AZA) and venetoclax (VEN), long-term survival for these patients remains poor. Additions to this new regimen may further improve patient outcomes. Overexpression of CD123, the alpha subunit of the IL-3 receptor, is seen in AML blasts. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprised of a high-affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. Preclinical data have demonstrated synergy between IMGN632 and AZA and/or VEN, including overcoming AZA/VEN resistance in murine AML models (Kuruvilla ASH 2020), supporting the clinical exploration of these combinations. Doublets of IMGN632 with both AZA and VEN were studied in AML patients and supported testing of the triplet of IMGN632, AZA, and VEN. Here we report the initial safety and anti-leukemia activity findings from this novel triplet. METHODS: This Phase 1b/2 study was designed to determine the safety, tolerability, and preliminary anti-leukemic activity of IMGN632 combined with AZA and VEN in patients with CD123-positive AML. To date, the triplet combination escalation consists of 5 cohorts of IMGN632 plus AZA and VEN, each agent designated by "C" for IMGN632 dose in mcg/kg, "A" for AZA dose in mg/m2 x7 days, or "V" for VEN # of days at 400mg QD. Four cohorts dosed IMGN632 on Day 7 of each cycle (C15A50V8, C15A50V14, C15A75V21, C45A50V8), and one cohort dosed IMGN632 on Day 1 of each cycle (Day 1 C15A50V14). Responses are determined using modified ELN criteria with a 14-day count recovery window. RESULTS: At the time of this analysis, preliminary safety data are available for 35 relapsed or refractory (R/R) AML patients. The median age was 69y, 23% had secondary AML, 86% received prior intensive therapies, 37% that were refractory to first line therapy, and 51% had received prior VEN. Twenty-three percent of patients had FLT3 mutations. The toxicity profile was manageable in this R/R AML population with multiple prior therapies. The most common treatment emergent adverse events (TEAE) all grades [grade 3+ events] seen in >20% of patients were infusion-related reactions (IRR, 37% [3%]), febrile neutropenia (26% [23%]), hypophosphatemia (26% [3%]), dyspnea (26% [6%]), pneumonia (20% [14%]), and fatigue (20% [0%]). One patient in the Day 1 C15A50V14 cohort discontinued IMGN632 due to a TEAE (DLT IRR, resolved). Cytopenias and infections were consistent with those observed with the AZA+VEN regimen in this R/R population. No TLS, VOD, capillary leak or cytokine release were observed. 30-day mortality was 0%. Efficacy was seen across all cohorts/doses and schedules (efficacy evaluable population, n=29). The objective response rate (ORR) was 55% with a composite complete remission (CCR) rate of 31% (1 CR, 4 CRh, 2 CRp, 2 CRi). Higher intensity cohorts (IMGN632 dose 45 mcg/kg or 14-21 days of VEN) on the Day 7 schedule (n=20) were associated with higher response rates: ORR 75%, CCR rate 40% (Figure 1). At these higher intensity cohorts, in the VEN naïve subset (n=10), ORR/CCR rates were 100%/60%, respectively. Significant activity was also seen in the FLT3 mutant subset (n=7), with ORR/CCR rates of 100%/71%. CONCLUSION: With a manageable safety profile in this R/R AML population, the novel IMGN632 triplet demonstrated compelling anti-leukemia activity. Ongoing escalation cohorts aim to optimize safety and efficacy of the triplet therapy. Expansion proof-of-concept cohorts are planned in both relapsed and frontline AML patients (NCT04086264). Updated safety, efficacy, and PK data will be presented. Figure 1 Figure 1. Daver: Trillium: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Hanmi: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Aribi: Seagen: Consultancy. Montesinos: Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Roboz: Astex: Consultancy; Jazz: Consultancy; Glaxo SmithKline: Consultancy; Mesoblast: Consultancy; Blueprint Medicines: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Astellas: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding; Jasper Therapeutics: Consultancy; Celgene: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wang: Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Walter: Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Amgen, Inc.: Consultancy, Research Funding; Amphivena Therapeutics, Inc.: Current equity holder in publicly-traded company; Aptevo Therapeutics, Inc.: Consultancy, Research Funding; Arog Pharmaceuticals, Inc.: Research Funding; Astellas Pharma US, Inc.: Consultancy; BioLineRx, Ltd.: Consultancy, Research Funding; Boston Biomedical, Inc.: Consultancy; Bristol Myers Squibb, Inc.: Consultancy; Celgene, Inc.: Consultancy, Research Funding; Genentech, Inc.: Consultancy; GlaxoSmithKline, Inc.: Consultancy; ImmunoGen, Inc.: Research Funding; Janssen Global Services, LLC: Consultancy; Janssen Research & Development, Inc.: Research Funding; Jazz Pharmaceuticals, Inc.: Consultancy, Research Funding; Kite Pharma, Inc.: Consultancy; Kronos Bio, Inc.: Consultancy; Kura Oncology, Inc.: Research Funding; Macrogenics, Inc.: Research Funding; New Link Genetics: Consultancy; Pfizer, Inc.: Consultancy, Research Funding; Race Oncology Ltd.: Consultancy; Selvita: Research Funding; Stemline Therapeutics, Inc.: Research Funding. Jeyakumar: Jazz: Research Funding; Pfizer: Research Funding. DeAngelo: Abbvie: Research Funding; Blueprint Medicines Corporation: Consultancy; Incyte Corporation: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Agios: Consultancy; Amgen: Consultancy; GlycoMimetics: Research Funding; Shire: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy. Erba: Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Agios, Amgen, Astellas Pharma, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Covance (AbbVie): Other: Independent Review Committee ; AbbVie, Ag

High dose cytarabine (HIDAC) consolidation has demonstrated a survival benefit in patients with acute myeloid leukemia (AML). The increasing prevalence of obesity and the toxicity risk with this therapy renders important the quantification of potential risks with weight-based dosing in this patient population. The American Society of Clinical Oncology published recommendations on chemotherapy dosing in obese patients, but patients with leukemia were excluded from analysis. This was a retrospective comparison of safety and efficacy outcomes in obese and non-obese patients with AML who received HIDAC consolidation. Thirty-nine (41.9 %) patients received dose adjusted HIDAC in cycle 1. Nine of the 40 patients in the obese group received HIDAC dose-adjusted for obesity. The combined incidence of cycle delays, febrile neutropenia, or documented infection was 41.5 % in non-obese patients compared to 57.5 % in obese patients (p = 0.127). The median overall survival (OS) and event free survival (EFS) were not reached in both cohorts. The estimated 36-month overall survival was 76.4 % (95 % CI 0.623-0.905) in non-obese patients, compared to 66.1 % (95 % CI 0.472-0.85) in obese patients. There were no significant differences in safety or efficacy outcomes for obese versus non-obese patients who received HIDAC consolidation. For class III obesity, baseline dose-adjustments were more common.

Abstract Introduction Blast-phase (BP), or leukemic transformation is a rare and devastating complication of myeloproliferative neoplasms (MPNs) (primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), and post-PV/ET myelofibrosis). Patients with BP-MPNs have a poor prognosis with a median overall survival of less than 6 months, and there is no standard treatment regimen for these aggressive diseases (Dunbar et al, Blood. 2020). The development of hypomethylating agent (HMA)/venetoclax (Ven) combination offers new hope for some with AML, but has been relatively disappointing in BP-MPN, though data are limited and retrospective (Masarova et al, Blood Adv. 2021; Gangat et al, Am J Hematol. 2021). Here, we add our experience with several common treatment regimens for BP-MPN. Methods We retrospectively analyzed data from 39 consecutive patients with BP-MPNs diagnosed from December 2008 to February 2021 who received treatment at the University of Michigan. We included all patients with a previous diagnosis of MPNs who had ≥ 20% blasts in the peripheral blood or bone marrow, and subsequently received systemic therapy. One patient with a myeloid sarcoma was included as well. Disease characteristics at time of BP-transformation were noted. Patients were divided into the following groups based on 1 st-line induction therapy: 7+3 (daunorubicin and cytarabine), FLAG (fludarabine, high-dose cytarabine and G-CSF), hypomethylating agent only (decitabine or azacitidine), and HMA/Ven. Patients were followed for 2 years post-diagnosis. Differences in induction response were assessed using the Chi-square test. Differences in overall survival were calculated using the Kaplan-Meier regression with the log-rank test. Two patients who received alternate induction therapy outside of the four groups were not included in these analyses. Results The composite BP-MPN population had a median advanced age of 69 years old and a median ECOG performance status (PS) of 1. Most (97.4%) had received systemic treatment prior to their transformation for their MPN, with 71.8% receiving hydroxyurea and 41.0% receiving ruxolitinib. The rate of response (CR, CRi, MLFS) was highest in the HMA/Ven group at 42.9%, followed by FLAG (29.4%), HMA only (11.1%), and 7+3 (0%), p = 0.033 (Table 3). Despite the higher response rate, differences in 2-year OS were not significantly different among the 4 groups: 7+3 (25.0%), FLAG (7.7%), HMA (0%), HMA/Ven (20.0%) (p=0.92, Figure 1). Median time to relapse after achieving remission ranged from 2-10 months, and did not vary significantly based on induction regimen. Patients in the HMA and HMA/Ven groups had higher incidences of death with induction at 77.8% and 28.6%, respectively (Table 3). Conclusions The highest rates of response, including complete remission, were achieved with the combination of HMA and venetoclax compared to intensive induction chemotherapy or HMA alone. However, this did not translate into significant differences in OS, which is consistent with other retrospective reports. No responses were seen with 7+3 induction, though several patients were able to go on salvaged with other therapies and subsequent allogeneic stem cell transplantation thereafter. Finally, the baseline poor ECOG PS of the HMA group and borderline ECOG PS of the HMA/Ven group also contribute to their low survival rates.Larger, prospective studies comparing currently available treatment regimens in BP-MPN would be helpful, but ultimately new therapies are desperately needed for this high-risk disease. Figure 1 Figure 1. Disclosures Bixby: Takeda: Consultancy. Talpaz: Constellation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Grant/research support ; Celgene: Consultancy; Imago: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.