Frontline Acute Myeloid Leukemia Research Articles

The PedAL/EuPAL Project: A Global Initiative to Address the Unmet Medical Needs of Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia.

The prognosis of children with acute myeloid leukemia (AML) has improved incrementally over the last few decades. However, at relapse, overall survival (OS) is approximately 40-50% and is even lower for patients with chemo-refractory disease. Effective and less toxic therapies are urgently needed for these children. The Pediatric Acute Leukemia (PedAL) program is a strategic global initiative that aims to overcome the obstacles in treating children with relapsed/refractory acute leukemia and is supported by the Leukemia and Lymphoma Society in collaboration with the Children's Oncology Group, the Innovative Therapies for Children with Cancer consortium, and the European Pediatric Acute Leukemia (EuPAL) foundation, amongst others. In Europe, the study is set up as a complex clinical trial with a stratification approach to allocate patients to sub-trials of targeted inhibitors at relapse and employing harmonized response and safety definitions across sub-trials. The PedAL/EuPAL international collaboration aims to determine new standards of care for AML in a first and second relapse, using biology-based selection markers for treatment stratification, and deliver essential data to move drugs to front-line pediatric AML studies. An overview of potential treatment targets in pediatric AML, focused on drugs that are planned to be included in the PedAL/EuPAL project, is provided in this manuscript.

The future paradigm of HMA + VEN or targeted inhibitor approaches: sequencing or triplet combinations in AML therapy.

The routine use of next-generation sequencing methods has underscored the genetic and clonal heterogeneity of acute myeloid leukemia (AML), subsequently ushering in an era of precision medicine-based targeted therapies exemplified by the small-molecule inhibitors of FLT3, IDH1/IDH2, and BCL2. This advent of targeted drugs in AML has broadened the spectrum of antileukemic therapies, and the approval of venetoclax in combination with a hypomethylating agent has been a welcome addition to our AML patients unable to tolerate intensive chemotherapy. Mounting evidence demonstrates that molecularly targeted agents combined with epigenetic therapies exhibit synergistic augmented leukemic cell kill compared to single-agent therapy. With such great power comes greater responsibility in determining the appropriate frontline AML treatment regimen in a molecularly defined subset and identifying safe and effective combination therapies with different mechanisms of action to outmaneuver primary and secondary resistance mechanisms in AML.

Real World Use of Azacitidine and Venetoclax in Acute Myeloid Leukemia in Frontline and Relapse/Refractory Settings: A Multicentric Study from French Auraml Group

Azacytidine and venetoclax combination regimen (AZA/VEN) is the standard of care in frontline acute myeloid leukemia (AML) settings for unfit to intensive chemotherapy patients. However, AZA/VEN is also associated with an increased hematological toxicity compared to azacytidine alone. In this context, alternative AZA/VEN regimens emerged progressively based on each physician experience and local procedures. Moreover, AZA/VEN is also recognized as a valuable therapeutic option in relapse/refractory settings. In this multicentric study, we aimed to evaluate the efficacy and safety of various AZA/VEN regimen in frontline and relapse/refractory (R/R) patients diagnosed with AML in real life setting. We retrospectively analyzed 331 patients from 11 different French centers (Saint-Etienne, Clermont-Ferrand, Lyon (Hopital Lyon Sud, Centre Léon Bérard), Vichy, Annecy, Chambery, Valence, Bourgoin-Jallieu, Grenoble, Roanne) in Auvergne Rhône Alpes (AURA) region, between January 2019 and February 2023. Composite complete remission was defined as in VIALE-A trial. Measurable residual disease (MRD) negativity was defined as ≤ 10 -3 by flow cytometry (on bone marrow) and/or ≤ 10 -4 for NPM1 by RT-qPCR. Overall, the entire cohort was composed of 186 and 146 patients in frontline and R/R settings respectively. In frontline setting, median age was 74.5 (19.1-86.1) and ELN 2022 risk groups were favorable, intermediate and unfavorable in 14.5, 16.7 and 68.8% respectively. De novo AML, MRC-AML, post-MPN/MDS AML and t-AML were 32.4%, 29.7%, 23.2% and 14.5% respectively. After 6 cycles, median CRc, morphologic leukemia free state (MLFS) and refractory rate were 66.4%, 5.4% and 28.2% respectively. Regarding probability of CRc, there was no significant difference between favorable and intermediate ELN 2022 risk group. Within unfavorable risk group, only complex karyotype was associated with lower CRc rate ( figure 1). Venetoclax dosage (400mg vs 100mg/d) and duration per cycle (28 days vs 21 days vs others) did not influence significantly CRc rate probability and OS. With a median follow-up of 7.3 months, median overall survival (OS) was 12.4 months (IC95%: 3.4-18.5). There was no significant difference in terms of OS according to ELN 2022 risk group classification ( figure 2). Among unfavorable risk group, only patients with unfavorable karyotype had a worst OS (median OS: 4.9 months), while patients with secondary AML mutations had similar OS than favorable/intermediate risk group (19.5 vs 20.2 vs 18.2 months, p=0.32). Reaching MRD negativity at any time during the first 6 cycles was associated with a better OS (26.1 vs 10.3 months, p<0.001). In responding patients, 22/122 withdrew VEN after a median of 5 cycles (range:1-17), while continuing AZA, mainly due to excessive hematological toxicity. Relapse free survival was similar between patients who stopped compared to those who continued up to progression. In multivariate analysis, only ECOG (continuous, HR= 1.52, p=0.04), IDH status (WT vs MUT: HR = 3.13, p=0.04, normal karyotype (yes vs no, HR=0.25, p=0.04) and CR type (CRMRD- vs other, HR= 0.21, p=0.001) significantly influence OS, whereas ELN 2022 did not In R/R settings, CRc rate was 43.8% and OS was 7.9 months. As in frontline setting, venetoclax dosage and duration per cycle did not influence CRs rate and OS. Febrile neutropenia (FN) occurred in 52.9%, 35.1% and 27.1% in cycle 1,2 and 3, respectively. Toxic death rates (TDR) range from 16.6% prior 2020 to 8.6% in 2021 and 6.25% from 2022 to 2023 (p=0.01). In or outpatient management for cycle 1 did not influence FN incidence. Azole prophylaxis did not significantly influence FN incidence. During cycle 1, shorter venetoclax duration regimens (<21 days/cycle) was associated with lower FN (41.5 vs 54.8%, p=0.042) compared to ≥21 days VEN cycle. In this real life settings study, our results suggest that outcome in frontline AZA/VEN treated patients is mainly driven by deep responses. Alternative AZA/VEN regimens were not associated with lower response rate and overall survival, while reducing venetoclax exposure during cycle 1 may reduce FN incidence without significant consequences on CR rate. TDR reduction through time suggest a learning curve and might be related to physician's skills improvement regarding AZA/VEN dosage schedules and supportive care management. An update with additional patients and longer follow-up will be presented at the meeting.

Building on Foundations: Venetoclax-Based Combinations in the Treatment of Acute Myeloid Leukemia.

Frontline acute myeloid leukemia (AML) treatment is determined by a combination of patient and genetic factors. This includes patient fitness (i.e., comorbidities that increase the risk of treatment-related mortality) and genetic characteristics, including cytogenetic events and gene mutations. In older unfit patients, the standard of care treatment is typically venetoclax (VEN) combined with hypomethylating agents (HMA). Recently, several drugs have been developed targeting specific genomic subgroups of AML patients, enabling individualized therapy. This has resulted in investigations of doublet and triplet combinations incorporating VEN aimed at overcoming known resistance mechanisms and improving outcomes in older patients with AML. These combinations include isocitrate dehydrogenase-1/2 (IDH1/2) inhibitors (i.e., ivosidenib and enasidenib), fms-like tyrosine kinase 3 (FLT3) inhibitors (i.e., gilteritinib), anti-CD47 antibodies (i.e., magrolimab), mouse double minute-2 (MDM2) inhibitors, and p53 reactivators (i.e., eprenetapopt). This review summarizes ongoing trials aimed at overcoming known VEN resistance mechanisms and improving outcomes beyond that observed with HMA + VEN combinations in the treatment of AML.

Changing frontline AML treatment patterns from 2013 to 2022

The treatment patterns for patients with newly diagnosed acute myeloid leukemia (AML) were compared between 2013 and 16 and 2021–22 in a real-world setting. A significantly higher proportion of patients age 70 and over received non-intensive therapy (NIT) in 2021–22 as compared with 2013–16 (65 % vs 44 %, p = 0.014), with a corresponding reduction in the proportion receiving either intensive therapy or no antileukemic treatment. Treatment patterns among patients < age 70 were unchanged. The complete response rate in the NIT group was 69 % in 2021–22 vs. 24 % in 2013–16 (p < 0.001); the overall survival (OS) of NIT patients was 11.5 months in 2021–22 vs. 7.8 months in 2013–16. Older patients from rural areas were more likely to decline therapy than those from urban regions. The increase in the proportion of patients opting for NIT may be related to the availability of more effective treatment options. Although outcomes are improving, the OS with NIT remains suboptimal.

A phase 1b/2 study of pivekimab sunirine (PVEK, IMGN632) in combination with venetoclax/azacitidine or magrolimab for patients with CD123-positive acute myeloid leukemia (AML).

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 &lt; 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 &lt; 30-minute outpatient infusion. In Regimen C, patients will receive PVEK 0.045 mg/kg IV on D7 + azacitidine 75 mg/m2 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 .

P551: A PHASE 3, RANDOMIZED, OPEN-LABEL STUDY EVALUATING THE SAFETY AND EFFICACY OF MAGROLIMAB IN COMBINATION WITH AZACITIDINE IN PREVIOUSLY UNTREATED PATIENTS WITH TP53-MUTANT ACUTE MYELOID LEUKEMIA

Background: Magrolimab (Hu5F9-G4) is an antibody blocking CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancer cells, that eliminates leukemia stem cells by inducing tumor phagocytosis. Hypomethylating agents synergize with magrolimab by inducing “eat me” signals on leukemic blasts, thereby enhancing phagocytosis. Magrolimab with azacitidine (AZA) has shown encouraging activity in frontline acute myeloid leukemia (AML) unfit for intensive chemotherapy and myelodysplastic syndrome. In TP53-mutant (TP53m) AML, it demonstrated an objective response rate of 69%, complete response (CR) rate of 45%, and median overall survival (OS) of 12.9 months. The TP53 gene mutation is observed in approximately 10-15% of newly diagnosed AML and is associated with poor survival. The published first-line median OS in TP53m AML is 4-7 months, regardless of whether patients are treated with intensive chemotherapy or non-intensive approaches, such as a hypomethylating agent with venetoclax (VEN). AML patients harboring the TP53 gene mutation represent a significant unmet medical need. Aims: To evaluate the efficacy, safety, and tolerability of magrolimab+AZA vs physician’s choice of VEN+AZA or “7 + 3” chemotherapy in patients with previously untreated TP53m AML. Methods: This is a phase 3, randomized, open-label, multicenter study. Approximately 346 patients will be randomized (1:1) to magrolimab+AZA (experimental arm) or physician’s choice of VEN+AZA or 7 + 3 chemotherapy, based on patient fitness. Randomization will be stratified by appropriateness for non-intensive vs intensive therapy, geographic region (US vs non-US sites), and age (<75 vs ≥75 years). Patients are eligible if they are ≥18 years old with histologically confirmed AML with no prior antileukemic therapy, with at least one TP53 gene mutation that is not benign or likely benign (confirmed by central laboratory) or biallelic 17p deletions (based on a locally evaluated karyotype/fluorescence in situ hybridization report). During the first 28-day cycle, patients randomized to magrolimab+AZA will receive magrolimab intravenously (IV) at a priming dose of 1 mg/kg on days 1 and 4, 15 mg/kg on day 8, and 30 mg/kg on days 11, 15, and then weekly for 5 doses, followed by every other week beginning 1 week after the fifth weekly 30 mg/kg dose. For patients randomized to the VEN+AZA arm, VEN and AZA will be administered according to labeled indications. Patients treated with 7 + 3 chemotherapy will receive 1-2 induction cycle(s) with IV daunorubicin or idarubicin on days 1-3 and cytarabine 100 mg/m2 or 200 mg/m2 on days 1-7 followed by up to 4 consolidation cycles with high-dose cytarabine (3000 mg/m2). Patients receiving magrolimab+AZA or VEN+AZA will remain on treatment until disease progression, relapse, loss of clinical benefit, unacceptable toxicities, or stem cell transplant. Patients can undergo stem cell transplantation per investigator decision. The primary endpoint is OS in patients appropriate for non-intensive therapy, and the key secondary endpoint is OS in all patients. Results: Trial in progress. Summary/Conclusion: Patient enrollment is ongoing. Clinical trial information: NCT04778397.

Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in frontline TP53m AML patients: Phase 1b results.

7020 Background: Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cancer cells such as acute myeloid leukemia (AML). This blockade induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. We report data from a Phase 1b trial of magrolimab+AZA in frontline TP53-mutant ( TP53m) AML. Methods: Patients (pts) with frontline AML not suitable for intensive chemotherapy received IV magrolimab starting with a priming dose (1 mg/kg) followed by ramp-up to 30 mg/kg QW or Q2W as maintenance dose. AZA 75 mg/m2 was given IV or SC on Days 1–7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by ELN 2017 criteria. Results: 72 TP53m AML pts were treated (Table). Common all-grade TEAEs were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Most common Grade 3+ TEAEs were febrile neutropenia (37.5%), anemia (29.2%; Grade 3, 26.4%; Grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). Objective response rate (ORR) by intent-to-treat was 48.6% (33.3% CR, 8.3% CR with incomplete hematologic recovery [CRi] / CR with partial hematologic recovery [CRh], 1.4% morphologic leukemia-free state [MLFS], 5.6% partial response). Stable disease was reported in 16.7%, progressive disease (PD) in 5.6%. 30- and 60-day mortalities were 8.3% and 18.1%, respectively. Response assessment was unavailable in 4.2% who discontinued due to AEs and 6.9% due to other, prior to the C3D1 assessment. Median time to CR/CRi was 2.2 months (mos; range 1.7–7.2) and to CR was 3.0 mos (range 1.8–9.6). 45.2% (14/31) of evaluable CR/CRi/CRh/MLFS pts achieved negative MRD by flow cytometry (investigator reported). Of 24 CR patients, 8 had a longitudinal TP53 VAF assessment, and 5/8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to SCT in 9 pts (12.5%), PD 26 (36.1%), death 8 (11.1%), AE 13 (18.1%), and other 14 (19.4%). Median durations of CR and CR/CRi were 7.7 mos (95% CI: 4.7, 10.9) and 8.7 mos (95% CI: 5.3, 10.9), respectively. Median overall survival (OS) for the 72 pts was 10.8 mos (95% CI: 6.8, 12.8) with median follow up 8.3 mos. Conclusions: In high-risk frontline TP53m AML pts unsuitable for intensive chemotherapy, magrolimab+AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial in TP53m AML (ENHANCE-2; NCT04778397) of this combination vs standard of care is ongoing. Clinical trial information: NCT03248479. [Table: see text]

Checkpoint Inhibitors and Other Immune-Based Therapies in Acute Myeloid Leukemia.

Immune checkpoint inhibitors have been investigated in acute myeloid leukemia (AML) with an intent to harness the immune microenvironment components to generate an immune response against leukemia. Anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed cell death 1/programmed cell death ligand 1 antibodies have been evaluated in combination with low-intensity therapy and cytotoxic chemotherapy, both in the pretransplant and posttransplant settings. Although the objective response rates with programmed cell death 1- and programmed cell death ligand 1-based therapies have been relatively low, durable stable disease and hematologic improvement were noted in a subset of patients, important endpoints in patients with limited therapeutic options. Novel AML and myelodysplastic syndrome-specific checkpoints such as TIM3 antibodies in combination with azacitidine are showing encouraging efficacy, especially durability of response, in ongoing studies. Anti-CD47/SIRPα therapy in combination with azacitidine has shown encouraging efficacy and safety in frontline AML, especially in TP53-mutated AML, a population of significant unmet need. Other T cell-based immune therapies are under investigation. T-cell and natural killer cell bispecific and trispecific engagers have shown modest activity in patients with relapsed and/or refractory AML albeit with frequent cytokine release syndrome. Chimeric antigen receptor T-cell therapy showed immense success in many lymphoid malignancies and is being evaluated in AML. Future trials should be designed to select patients based on markers of response and tailor therapies according to predictive biomarkers.

A Phase II Study of CPX-351 Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed Acute Myeloid Leukemia (AML)

A Phase II Study of CPX-351 Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed Acute Myeloid Leukemia (AML)

Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Real World Survival Outcomes of CPX-351 Versus Venetoclax and Azacitadine for Initial Therapy in Adult Acute Myeloid Leukemia

Real World Survival Outcomes of CPX-351 Versus Venetoclax and Azacitadine for Initial Therapy in Adult Acute Myeloid Leukemia

A Phase 3, Randomized, Open-Label Study Evaluating the Safety and Efficacy of Magrolimab in Combination with Azacitidine in Previously Untreated Patients with TP53-Mutant Acute Myeloid Leukemia

A Phase 3, Randomized, Open-Label Study Evaluating the Safety and Efficacy of Magrolimab in Combination with Azacitidine in Previously Untreated Patients with TP53-Mutant Acute Myeloid Leukemia

A Phase 1b/2 Study of the CD123-Targeting Antibody-Drug Conjugate IMGN632 As Monotherapy or in Combination with Venetoclax and Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia

A Phase 1b/2 Study of the CD123-Targeting Antibody-Drug Conjugate IMGN632 As Monotherapy or in Combination with Venetoclax and Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia

Evaluating the Safety of Outpatient Ramp up of Venetoclax in Acute Myeloid Leukemia and Myelodysplastic Syndrome

IntroductionVenetoclax, a selective b-cell lymphoma 2 (BCL2) inhibitor, has changed the landscape of treatment in newly diagnosed acute myeloid leukemia (AML) elderly patients. In addition, it has shown promising efficacy in treatment-naive and relapsed/refractory (r/r) myelodysplastic syndrome (MDS) as well as r/r AML. Unique toxicities of venetoclax include tumor lysis syndrome (TLS) due to the rapid apoptotic effect by BCL2 inhibition. Although TLS is less frequently reported in AML, due to the fatalities from TLS reported in chronic lymphocytic leukemia patients, inpatient hospitalization during initial venetoclax dose ramp up is recommended. Hydroxyurea or leukapheresis can also be used to achieve a white blood cell (WBC) count of less than 25,000 prior to initiating venetoclax. At NYU Langone Health (NYULH), patients are initiated on venetoclax dose ramp up in the outpatient setting regardless of WBC count due to the low incidence of TLS. The aim of this study is to assess the safety of outpatient venetoclax dose escalation in our AML and MDS patients.Methods/ResultsThis was an institutional review board approved, descriptive, retrospective medical chart review of 60 adult patients who received venetoclax dose ramp up in the outpatient setting at NYULH and NYU Long Island from March 1, 2017 to March 01, 2021. Patients were included if they were 18 years and older, received venetoclax in combination with either hypomethylating agents (HMA) or low-dose cytarabine in the outpatient setting, and had a documented diagnosis of either de novo AML, r/r AML, newly diagnosed high-risk MDS, or r/r MDS. The primary endpoint was the number of patients demonstrating laboratory or clinical TLS as defined by Cairo-Bishop Criteria described by Howard and colleagues. Secondary endpoints included hospital admission within two weeks of initiating venetoclax therapy. If patients did not have laboratory values obtained within one week of starting venetoclax, but had continued hematology follow-up with the NYU health system, it was assumed that these patients did not experience laboratory or clinical TLS.One patient was counted as two individual patients because venetoclax was initiated as initial frontline AML treatment, followed by re-trial for relapsed disease. The median age was 74 years (IQR, 66-83). Most patients (24) had newly diagnosed AML (40%) followed by 17 patients (28.3%) with newly diagnosed MDS, 14 patients (23.3%) with r/r AML, and 5 patients (8.3%) with r/r MDS. The median total WBC count prior to initiating venetoclax was 2.25 x 10^3 cells/uL (IQR, 1.40-7) with a median blast count in the bone marrow of 25% (IQR, 11.5-53). Two patients had an initial WBC count of greater than 25. Thirty-six (60%) patients had a Carlson Comorbidity Index score of 5 or greater.Decitabine was the most common combination agent used (50%), followed by azacitidine (48.3%), and low-dose cytarabine (1.7%). The majority of patients, 39 (65%) were prescribed the standard dosing ramp up schedule, with 15 patients (25%) had venetoclax initiated during cycle two or thereafter. Thirty-seven (61.7%) patients ramped up to the full venetoclax dose (either 400mg or 600mg). The most common reasons for dose reductions included drug-drug interactions (7 patients), neutropenia or anemia (7 patients), and general tolerance (5 patients). Thirty-seven (61.7%) patients were prescribed allopurinol prophylaxis. No patients received rasburicase prior to initiating venetoclax.Only 1 patient (1.67%) experienced both laboratory and clinical tumor lysis and required intravenous hydration in outpatient clinic. Three additional patients (5%) required TLS directed treatment, but did not meet TLS definition. Of note, 8 patients (13.3%) did not have any laboratory values checked between days 1-7 of starting venetoclax. No patients were hospitalized within two weeks of venetoclax initiation due to TLS.ConclusionAdministering venetoclax dose ramp up in the outpatient setting avoids need for hospitalization and appears to be safe in patients with AML and MDS. Limitations of this study include the heterogeneous population and the retrospective nature of the study. Although 35% of our patients were not prescribed the standard venetoclax ramp up dose, this highlights the existing challenges of treating elderly AML and MDS patients. DisclosuresAbdul Hay: Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau. OffLabel Disclosure:To assess the safety of outpatient venetoclax ramp up in both newly diagnosed & relapsed/refractory acute myeloid leukemia & myelodysplastic syndrome

Frontline treatment patterns and outcomes among older adults with acute myeloid leukemia: A population-based analysis in the modern era.

Traditionally, conventional induction chemotherapy has been the primary frontline treatment for acute myeloid leukemia (AML); however, older adults are often poor chemotherapy candidates. Recently, several nonconventional frontline AML regimens, including hypomethylating agents, the BCL-2 inhibitor venetoclax, and targeted therapies, have emerged, and they may offer new options for older adults. This study was aimed at describing treatment patterns and outcomes of older adult AML in a modern population-based cohort. This study evaluated patients aged ≥60 years with a first primary diagnosis of AML (2014-2017) in the California Cancer Registry linked to inpatient hospitalizations. Multivariable regression examined factors associated with the frontline treatment regimen and survival. In all, 3068 patients were included; 36% received frontline therapy with a conventional chemotherapy backbone, 42% received nonconventional therapy, and 22% received no treatment. The use of nonconventional therapy increased over time from 38% of patients in 2014 to 47% in 2017 (P < .001). In multivariable analyses, receipt of treatment was associated with an age younger than 80 years, fewer than 2 comorbidities, and care at a National Cancer Institute-designated cancer center (NCI-CC). Compared with conventional chemotherapy, nonconventional therapy was associated with Black race/ethnicity, public health insurance, fewer hospital admissions, and fewer inpatient days. Receiving frontline therapy at an NCI-CC was independently associated with superior overall survival. Using a population-based approach, this study has demonstrated that patterns of care for frontline AML treatment in older adults are changing, with increasing use of nonconventional therapies. A significant proportion of older adults remain untreated. At the population level, there remain opportunities to increase therapy access for older adults with AML.

Nivolumab (Nivo) with Azacytidine (AZA) in Patients (pts) with Relapsed Acute Myeloid Leukemia (AML) or Frontline Elderly AML

Nivolumab (Nivo) with Azacytidine (AZA) in Patients (pts) with Relapsed Acute Myeloid Leukemia (AML) or Frontline Elderly AML

Utilization of Hypomethylating Agents and Associated Outcomes in Elderly Acute Myeloid Leukemia (AML) Patients: A Population Based Study

Objective: No head to head randomized clinical trial has previously been conducted to compare the clinical outcomes between the hypomethylating agents (HMAs), azacitidine and decitabine, in the treatment of older patients with Acute Myeloid Leukemia (AML). Our objective is to compare the survival outcomes between both HMAs by using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database.Methods: Patients 1) had their index diagnosis between January 1, 2007 and December 31, 2014, 2) were continuously enrolled in Medicare Part A, Part B and Part D, and 3) were not enrolled in Medicare Advantage at the time of index AML diagnosis. Kaplan-Meier curves and Cox proportional hazards regression assessed overall survival by treatment.Results: Of the 3,922 patients who received front-line AML treatment, 28% and 29% received decitabine and azacitidine, respectively. The median age (mean) of azacitidine and decitabine was 75 (75) and 74 (74) years, respectively. The racial distribution was also similar with 88% and 86% of whites in the azacitidine and decitabine groups, respectively. 41% of azacitidine and 40% of decitabine treated patients were male. The median overall survival (mOS) of patients who received azacitidine and decitabine was 213 (95% confidence interval (CI): 195-236) and 217 (CI: 194-234) days, respectively. In patients <75 years, the mOS of azacitidine and decitabine treated patients was 246 (CI: 220-283) and 252 (CI: 227-289) days, respectively. In patients ≥75 years, the mOS of azacitidine and decitabine treated patients was 185 (CI: 158-210) and 179 (CI: 152-201) days, respectively. In a multivariate analysis, significant survival benefits were noted in younger patients and those with transfusion independence at time of diagnosis. Adjusting for age, gender, time to treatment and transfusion status, the hazard ratio for death for decitabine vs. azacitidine was 1.02 (CI: 0.94-1.11, p=0.65).Conclusions: This population-based study showed that both azacitidine and decitabine can be considered as equivalent standards of care with comparable survival outcomes for the management of older patients with AML who are unfit for intensive chemotherapy. [Display omitted] DisclosuresMehra:Janssen: Employment. He:Janssen: Employment. Potluri:SmartAnalyst Inc.: Employment; Janssen: Consultancy, Research Funding. Loefgren:Janssen: Employment.

Does patient fitness play a role in determining first-line treatment of acute myeloid leukemia?

The treatment choice for newly diagnosed patients with acute myeloid leukemia (AML) is no longer straightforward. Historically, patient fitness has been a major driver of the initial therapy decision based on the belief that intensive chemotherapy would be the optimal choice if a patient were "fit" enough to receive it. Tools based on chronological age, performance status, and comorbidities have been developed to help estimate patient fitness. With newer approved therapies that include nonintensive options such as IDH1 inhibition or less intensive options such as hypomethylating agent (HMA)- or low-dose cytarabine (LDAC)-based combinations with venetoclax, the choice of frontline AML therapy places more emphasis on disease-specific features, including cytogenetics and mutational profile. Moreover, newer treatments have higher response rates than what has been expected with older nonintensive options such as LDAC or HMA monotherapy. We present cases of three patients with AML with varying cytogenetic and molecular risks to demonstrate the important but changing role of patient fitness in the current era of expanding therapeutic options.

Analysis of Practice Patterns Among Experts and Community Healthcare Providers for the Treatment of Acute Myeloid Leukemia

Analysis of Practice Patterns Among Experts and Community Healthcare Providers for the Treatment of Acute Myeloid Leukemia