A Study Evaluating the Safety and Efficacy of Idasanutlin in Combination With Cytarabine and Daunorubicin in Patients Newly Diagnosed With Acute Myeloid Leukemia (AML) and the Safety and Efficacy of Idasanutlin in the Maintenance of First AML Complete Remission

2019 ◽  
Author(s):  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Newly Diagnosed ◽  
Safety And Efficacy ◽  
Acute Myeloid

scholarly journals Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia

2021 ◽  
Vol 39 (1) ◽  
pp. 57-65
Author(s):  
Courtney D. DiNardo ◽  
Anthony S. Stein ◽  
Eytan M. Stein ◽  
Amir T. Fathi ◽  
Olga Frankfurt ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Adverse Events ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Qt Prolongation ◽  
Newly Diagnosed ◽  
Isocitrate Dehydrogenase 1 ◽  
Grade 3 ◽  
Acute Myeloid

PURPOSE Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (m IDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922 ). RESULTS Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.

Plasma Exosomes As Markers of Residual Disease in Patients with Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2357-2357
Author(s):  
Michael Boyiadzis ◽  
Chang Sook Hong ◽  
Theresa L Whiteside
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Protein Content ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Molecular Profile ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Acute Myeloid

Abstract Background: Exosomes are virus-size (30–100 nm in diameter) membrane-bound microvesicles that are formed within the endocytic compartments and via fusion of multivesicles bodies are released into extracellular space. The exosomal cargo includes proteins/glycoproteins expressed on the cell membrane as well as molecules and soluble factors present in the cytosol of parental cells. While exosome secretion occurs under physiologic conditions, and all cells are capable of their release, tumor cells are avid exosome producers. Patients newly diagnosed with acute myeloid leukemia (AML) prior to any therapy have higher levels of exosomes compared to normal controls (NC). We hypothesize that the molecular content of isolated exosomes, which are thought to mimic that of leukemic blasts, could be informative about the presence in the bone marrow of leukemic blasts that might avoid detection by conventional hematopathological assays. Methods: Samples of venous blood (20-50 mL) were obtained from patients newly diagnosed with AML prior to any treatment (n=13), after completion of initial induction chemotherapy in patients who achieved complete remission (n=8), during consolidation therapy and age-matched healthy volunteers. Exosome fractions were isolated from plasma by exclusion chromatography on Sephadex G50 columns followed by ultracentrifugation. Exosome protein content was determined and expressed in µg protein/mL plasma. Isolated exosomes were characterized by western blots for expression of classical exosomal markers and for expression of novel myeloid cell surface markers associated with AML, interleukin-3 receptor a chain (CD123) and C-type lectin-like molecule-1 (CLL-1). Results: The exosome fractions isolated from AML patients’ plasma at diagnosis had a considerably greater mean protein content (81.5 ± 10.8 μg protein/mL plasma) than did exosome fractions isolated from the plasma of NC (13.1 ± 2.4 μg protein/mL plasma) with p < 0.005. The molecular profile of exosomes isolated from plasma of AML patients at diagnosis was distinct from that of exosomes isolated from plasma of NC. In addition to classical exosomal markers (MHC class I molecules, LAMP-1, CD81) exosomes isolated from AML patients at diagnosis contained CD34, CD117, CD123 and CLL-1. The exosome fractions isolated from the patients’ plasma who achieved complete remission (n=8) remained elevated, similar to the levels at the time of AML diagnosis (78.5 vs 77.5 μg protein/mL plasma). Exosomes in AML patients who achieved complete remission and in patients receiving consolidation therapy when leukemic blasts are undetectable in the bone marrow by conventional hematopathological methods contained CD123 and CLL-1. Conclusions: Exosomes in AML patients have a unique and distinctive molecular profile. The exosomal profile suggest the presence of residual disease in patients considered to have achieved complete remission by conventional hematopathologic assays. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3895-3895
Author(s):  
Hannah Asghari ◽  
Dasom Lee ◽  
Yehuda E. Deutsch ◽  
Onyee Chan ◽  
Najla Al Ali ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Group ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Acute Myeloid

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3. Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: 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; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.

Phase 2 Trial of G-CSF Priming, Clofarabine, and High Dose Cytarabine (GCLAC) for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) or Advanced Myelodysplastic Syndrome or Advanced Myeloproliferative Neoplasm,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3617-3617
Author(s):  
Pamela S Becker ◽  
Bruno C. Medeiros ◽  
Frederick R. Appelbaum ◽  
Bart Lee Scott ◽  
Paul C. Hendrie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Pulmonary Toxicity ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasm ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 3617 Clofarabine and cytarabine combinations have been effective in the treatment of adult acute myeloid leukemia (AML) in both the relapsed/refractory and upfront settings. Based on our results with GCLAC (G-CSF priming, clofarabine, and high dose cytarabine) in a trial for relapsed/refractory AML (Becker et al. Br J Haematol in press), we are currently testing this regimen in newly diagnosed patients age < 65. The G-CSF dose is 5 mcg/kg/day by subcutaneous injection beginning the day prior to chemotherapy, clofarabine 30 mg/m2/day × 5 and cytarabine 2 gm/m2/day × 5. Second induction with the same regimen was permissible if marrow blasts over 5% persisted on day 21 or thereafter. Consolidation courses were administered for up to 3 cycles, with clofarabine at a dose of 25 mg/m2/day × 4 days and cytarabine 2 gm/m2/day × 4 days. The primary objectives of this trial are to estimate rates of CR (complete remission) and EFS (event free survival). A stopping rule would be imposed if there was reasonable evidence that the CR rate was inferior to that obtained with standard induction 7+3, 70% (Fernandez et al. NEJM 2009; 361:1249–59). Absent early stopping, 50 patients will be treated. Twenty-five patients with non-APL AML, RAEB2, CMML2, or myelofibrosis with >10% blasts have been treated thus far; their median age is 52, range 22–63. Eleven patients had antecedent hematologic disorders(AHD). Four patients had poor risk cytogenetics, four patients had normal cytogenetics with Flt3+, and 5 patients had good risk cytogenetics. The most significant grade 3/4 toxicity occurring in 2 patients, was a constellation of pulmonary infiltrates, hypoxia, and diffuse alveolar hemorrhage that responded to steroids. This incidence is not dissimilar to the pulmonary toxicity described with single-agent high-dose cytarabine (Andersson et al. Cancer 1990; 65:1079–84). Pulmonary toxicity has not occurred in 8 subsequent patients given steroid premedication. The other grade 3 adverse events (AEs) included pneumonia (8), viral respiratory infection (6), abscess (4), bacteremia (13), and one additional grade 4 AE was septic shock. There has been no treatment related mortality. Fifteen of 17 currently evaluable patients have achieved CR, all but one with a single course, and 1 additional patient attained CRp (complete remission with incomplete platelet recovery). Using a model that accounts for cytogenetics, age, AHD, and organ function, the observed CR rate of 88% (95% CI 64%to 95%) exceeds the expected rate of 61% had the same patients received other high-dose cytarabine containing regimens but without clofarabine. Given the recent shortage of daunorubicin and the lack of assurance that an idarubicin dose (18mg/m2) that would be the nominal equivalent of 90mg/m2 daunorubicin is safe (Garcia-Manero et al. Haematologica 2002; 87:804–7), GCLAC may be a suitable alternative induction regimen for newly diagnosed AML and advanced myelodysplastic syndrome or myeloproliferative neoplasm. Disclosures: Becker: Sanofi-Oncology: Research Funding. Off Label Use: Clofarabine is FDA approved for treatment of relapsed pediatric acute lymphoblastic leukemia.

Comparison of idarubicin + ara-C–, fludarabine + ara-C–, and topotecan + ara-C–based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3575-3583 ◽  
Author(s):  
Elihu H. Estey ◽  
Peter F. Thall ◽  
Jorge E. Cortes ◽  
Francis J. Giles ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Confidence Interval ◽  
Myeloid Leukemia ◽  
Refractory Anemia ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
New Treatments ◽  
Acute Myeloid

Abstract It has been unclear whether regimens containing topotecan + ara-C (TA) or fludarabine + ara-C (FA) ± idarubicin are superior to regimens containing idarubicin + ara-C (IA) without either fludarabine or topotecan for treatment of newly diagnosed acute myeloid leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t), or RAEB. Of 1279 patients treated here for these diagnoses between 1991 and 1999, 322 received IA regimens, 600 FA regimens, and 357 TA regimens. All regimens used ara-C doses of 1 to 2 gm/m2/d, given by continuous infusion in IA, and over 2 to 4 hours in FA and TA. Complete remission (CR) rates were lower with FA (55%) and TA (59%) than with IA (77%). Both event-free survival (EFS) in CR and survival were shorter: median EFS in CR (95% confidence interval) was 63 weeks (range, 55-76 weeks) for IA, 40 (range, 31-46 weeks) for FA, and 36 (range, 27-44 weeks) for TA; median survival was 77 weeks (range, 57-88 weeks) for IA, 30 (range, 27-35 weeks) for FA, and 41 (range, 35-50 weeks) for TA. These trials were not randomized, and patients with worse prognoses were disproportionately given the FA and TA regimens. Nonetheless, after accounting for prognosis the FA and TA regimens remained highly significantly associated with lower CR rates, shorter EFS in CR, and shorter survival. Accounting for possible effects of individual trials within each of the IA, FA, and TA groups did not alter these findings. It is unlikely that, as given here, either FA or TA is, in general, superior to IA, highlighting the need for new treatments.

scholarly journals Effect of Complete Remission and Responses Less Than Complete Remission on Survival in Acute Myeloid Leukemia: A Combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study

2010 ◽  
Vol 28 (10) ◽  
pp. 1766-1771 ◽  
Author(s):  
Roland B. Walter ◽  
Hagop M. Kantarjian ◽  
Xuelin Huang ◽  
Sherry A. Pierce ◽  
Zhuoxin Sun ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Eastern Cooperative Oncology Group ◽  
Cancer Center ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Platelet Recovery ◽  
Southwest Oncology Group ◽  
Acute Myeloid

PurposeIt is known that complete remission (CR) prolongs survival in acute myeloid leukemia (AML). In 2003, less stringent response categories were introduced, most notably CR with incomplete platelet recovery (CRp). Although the significance of CRp for survival remains unclear, reports of AML trials frequently combine CR with CRp rather than considering CR as a separate entity.Patients and MethodsThis practice led us to retrospectively examine the effect of CR on outcome in newly diagnosed AML, by using data from 6,283 patients treated on Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) protocols or at M. D. Anderson Cancer Center. This effect was then contrasted with the effect of CRp in the M. D. Anderson Cancer Center cohort.ResultsAt least 94% of patients receiving cytarabine-based therapy and surviving for more than 3 or 5 years achieved a CR with either initial or salvage therapy; limited data suggest the same for patients receiving initial therapies that did not contain cytarabine. Patients with CR were more likely to live beyond 3 or 5 years than patients with CRp. The likelihood of achieving a CR rather than CRp was greater for patients with AML who had better prognosis. After adjustment for covariates, the relapse-free survival of patients achieving CR was longer than that of patients achieving CRp, whereas patients with CRp survived longer than those with resistant disease.ConclusionOur data indicate that CR is of unique clinical significance and should be reported as separate response in trials of newly diagnosed AML. Nonetheless, our findings validate CRp as a clinically meaningful response.

scholarly journals Levels and Clinical Significance of Regulatory B Cells and T Cells in Acute Myeloid Leukemia

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Qiaofeng Dong ◽  
Guosheng Li ◽  
Claudio Fozza ◽  
Shuli Wang ◽  
Shuhuan Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Newly Diagnosed ◽  
Regulatory B Cells ◽  
Foxp3 Mrna ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy, whose immunological mechanisms are still partially uncovered. Regulatory B cells (Bregs) and CD4+ regulatory T cells (Tregs) are subgroups of immunoregulatory cells involved in modulating autoimmunity, inflammation, and transplantation reactions. Herein, by studying the number and function of Breg and Treg cell subsets in patients with AML, we explored their potential role in the pathogenesis of AML. Newly diagnosed AML patients, AML patients in complete remission, and healthy controls were enrolled. Flow cytometry was used to detect percentages of Bregs and Tregs. ELISA was conducted to detect IL-10 and TGF-β in plasma. The mRNA levels of IL-10 and Foxp3 were measured with RT-qPCR. The relationship of Bregs and Tregs with the clinicopathological parameters was analyzed. There was a significant reduction in the frequencies of Bregs and an increase of Tregs in newly diagnosed AML patients compared with healthy controls. Meanwhile, patients in complete remission exhibited levels of Bregs and Tregs comparable to healthy controls. Furthermore, compared with healthy controls and AML patients in complete remission, newly diagnosed AML patients had increased plasma IL-10 but reduced TGF-β. IL-10 and Foxp3 mRNA levels were upregulated in the newly diagnosed AML patients. However, there were no significant differences in IL-10 and Foxp3 mRNA levels between patients in complete remission and healthy controls. Bregs and Tregs have abnormal distribution in AML patients, suggesting that they might play an important role in regulating immune responses in AML.

scholarly journals Evaluating Venetoclax Treatment Duration When Combined with Hypomethylating Agents in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4412-4412
Author(s):  
Emma Uchida ◽  
Matthew M Lei ◽  
Andrew M. Brunner ◽  
Amir T. Fathi ◽  
Jessie Signorelli
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Allogeneic Transplant ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background: Current literature recommends 28-day cycles of a hypomethylating agent (HMA) with continuous daily venetoclax (Ven) in select patients with newly diagnosed acute myeloid leukemia (AML). Key adverse events observed with azacitidine-Ven were grade ≥ 3 thrombocytopenia, neutropenia, and febrile neutropenia. Emerging data recommends HMA-Ven in relapsed/refractory (r/r) high-risk myelodysplastic syndrome (MDS) with a Ven duration ranging from 14-28 days of a 28-day cycle. Predominant grade ≥ 3 treatment emergent adverse events (TEAEs) also included cytopenias in this patient population. As the combination of HMA-Ven for patients with MDS and AML is increasingly utilized, practice variations in the initial duration of Ven requires evaluation. This study aims to characterize the safety profile with continuous or modified duration Ven after complete remission (CR), complete remission with incomplete hematologic recovery (CRi) or cycle 3 to further assess the safety profile of HMA-Ven due to treatment instead of disease. Methods: This is a retrospective, single center study of patients &gt; 18 years of age with AML or MDS receiving HMA-Ven between December 1, 2017 - January 31, 2021. Patients were excluded if enrolled in an investigational protocol or received therapy at an outside hospital. To capture treatment-related neutropenia, thrombocytopenia, and other safety endpoints, patients were excluded if they received &lt; 3 cycles of HMA-Ven, as cytopenias could be due to disease burden. Data was collected from day -21 until the completion of cycle 6 or last completed cycle. The primary end point was grade &gt; 3 neutropenia for &gt; 7 days. Secondary endpoints included grade &gt; 3 anemia or thrombocytopenia for &gt; 7 days, incidence of febrile neutropenia, antimicrobial use, dose interruption or delay, dose or duration modification, therapy discontinuation, and assessment of CR and CRi. Descriptive statistics were utilized to describe outcomes and safety endpoints were graded with the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v.5.0). Results: 25 patients were included in analysis. The median age was 66 years (range 20-84) and 12% (n=3) had a diagnosis of MDS while 88% (n=22) had a diagnosis of AML. Most patients with AML had poor cytogenetic risk (n=18, 84%) and 28% (n=7) were treatment naïve. Prior therapies are outlined in Table 1. Ven was initiated with a 14-day duration in 60% (n=15) of patients, including 3 patients with MDS, 4 patients with r/r AML, and 4 patients with r/r AML with a prior allogeneic transplant. Many patients required a subsequent duration change of Ven throughout the evaluation period (n=13, 52%). Treatment delays of &gt; 7 days occurred in 60% (n=15) of patients. 12 patients (48%) achieved CR or CRi and accounted for 45 evaluated cycles. Of the 12 patients, 4 started with 28-day ven, 1 with 21-day, and 7 with 14-day. Of the patients who achieved CR or CRi, there were 32 cycles with Ven 14-day durations, 7 cycles with 21-day duration, and 6 cycles of 28-day duration. Grade 3 or higher neutropenia for &gt; 7 days was observed in 72% (n=23) of the 14-day durations and 100% of the 21-day and 28-day Ven durations. Grade 3 or higher thrombocytopenia and anemia was most common in the 28-day duration Ven at 83% (n=5) and 50% (n=3), respectively. Febrile neutropenia and treatment with antibiotic therapy had higher incidence of 67% (n=4) in the 28-day Ven duration. Most patients received treatment with antibiotic therapy (75%, n=9) and antifungal therapy (67%, n=8) after achieving CR or CRi on HMA-Ven. In those with newly diagnosed AML, 29% (n=2) and 57% (n=4) achieved CR and CRi respectively. 67% (n=2) of the MDS patients and 27% (n=4) of the r/r AML population achieved CRi. Of the 9 patients with prior HMA exposure, 2 patients achieved CRi. Conclusions: There was a high incidence of grade 3 or higher cytopenias, but a trend toward increased neutropenia, thrombocytopenia, febrile neutropenia, and infectious complications were observed in those receiving a 21-day or 28-day Ven duration after CR or CRi compared to those receiving a 14-day duration of Ven. Early decreased durations of Ven and further decreases outside the prescribing information after patients are in CR may be a reasonable and safe option for patients who are not likely to tolerate continuous Ven, such as those with prior MDS, r/r disease, or patients who have received prior allogeneic transplant. This requires further investigation. Figure 1 Figure 1. Disclosures Lei: AbbVie: Honoraria; Epizyme: Honoraria; Intervention Insights: Consultancy; Fresenius Kabi: Consultancy. Brunner: GSK: Research Funding; Agios: Consultancy; Keros Therapeutics: Consultancy; AstraZeneca: Research Funding; Aprea: Research Funding; Acceleron: Consultancy; Janssen: Research Funding; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Fathi: Kite: Consultancy, Honoraria; Foghorn: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Trillium: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria. Signorelli: Bristol Myers Squibb: Consultancy; AbbVie: Honoraria.

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