[Safety and efficacy of 7-day administration of azacitidine and venetoclax combination therapy (7+7 therapy)].

Acute myelogenous leukemia (AML) has a poor prognosis in patients who are ineligible for intensive chemotherapy. The combination of azacitidine and venetoclax has been shown to have high overall efficiency and remission rates, even in patients ineligible for aggressive chemotherapy. However, myelosuppression is often prolonged after treatment, and infection can also occur. Severe myelosuppression is often addressed by dose titration, but specific dose titration methods have not been clarified. We used the standard induction therapy with azacitidine plus venetoclax, and if blasts decreased to 20% or less, switched to 7+7 therapy to shorten venetoclax to 7 days starting from the next cycle. In the 19 patients we treated (median age 80 years), response rate above MLFS was 100%, CR 57.9%, CRc (CR+CRi) 78.8%, median OS 693 days, median PFS 458 days, and median OS was not reached in previously untreated patients. This indicates that 7+7 is a highly effective and well-tolerated treatment.

Reduced dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia following intensive or low-intensity induction: a single-centre, single-arm, phase 2 trial.

BACKGROUND: Patients with acute myeloid leukaemia have high rates of relapse, especially if they are unable to complete standard consolidation strategies or allogeneic haematopoietic stem-cell transplantation (HSCT). The phase 3 QUAZAR AML-001 study showed an overall survival benefit with oral azacitidine maintenance. The BCL2 inhibitor venetoclax is highly active in acute myeloid leukaemia and synergistic with azacitidine. We aimed to evaluate the efficacy and safety of low dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia. METHODS: We performed a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center in the USA. Eligible patients were adults (aged ≥18 years) with a WHO 2016 diagnosis of acute myeloid leukaemia in complete remission or complete remission with incomplete blood count recovery following intensive or low-intensity induction and not immediately eligible for HSCT. Eastern Cooperative Oncology Group performance status had to be 3 or less. Patients were assigned to maintenance therapy with azacitidine 50 mg/m2 intravenously or subcutaneously for 5 days and venetoclax 400 mg orally for 7 days or 14 days. The primary outcome was relapse-free survival. The study was closed early due to slow accrual. All patients were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04062266). FINDINGS: Between Sept 26, 2019, and Oct 26, 2022, 35 patients were enrolled, of whom 25 (71%) were assigned to cohort 1 following intensive induction and ten (29%) to cohort 2 following low-intensity induction. Of 35 patients, 18 (51%) were male and 17 (49%) were female. The median age was 55 years (IQR 41-62). The median number of cycles given was 9 (IQR 2-22) and median follow-up time was 23·3 months (IQR 9·0-30·0). The median relapse-free survival was not reached (95% CI 20·2 to not calculable) in the full cohort, not reached (29·1 to not calculable) in cohort 1, and 30·3 months (16·5 to not calculable) in cohort 2. The 2-year relapse-free survival was 65% (95% CI 50-85) in the full cohort, 71% (53-94) in cohort 1, and 52% (27-100) in cohort 2. The most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=6), lung infection (n=4), leukopenia (n=4), and neutropenia (n=3). No deaths occurred during maintenance therapy. INTERPRETATION: Low dose azacitidine plus venetoclax is a feasible maintenance strategy in acute myeloid leukaemia following intensive and low-intensity induction. FUNDING: University of Texas MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech.

Efficacy and safety of azacitidine in pediatric patients with newly diagnosed advanced myelodysplastic syndromes before hematopoietic stem cell transplantation in the AZA-JMML-001 trial.

Here we report efficacy, pharmacokinetics, and safety data obtained in treatment-naive, pediatric patients with newly diagnosed advanced MDS receiving azacitidine in the AZA-JMML-001 study. The primary endpoint was response rate (proportion of patients with complete response [CR], partial response [PR], or marrow CR, sustained for ≥4 weeks). Of the 10 patients enrolled, one had an unconfirmed marrow CR and none had confirmed responses after three cycles; the study was therefore closed after stage 1. Azacitidine was well tolerated. The lack of efficacy of azacitidine in pediatric patients with newly diagnosed advanced MDS highlights the need for effective new treatments in these patients.

Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia.

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.

Hypomethylating agent monotherapy in core binding factor acute myeloid leukemia: a French multicentric retrospective study.

Very few data are available about hypomethylating agent (HMA) efficiency in core binding factor acute myeloid leukemias (CBF-AML). Our main objective was to evaluate the efficacy and safety of HMA in the specific subset of CBF-AML. Here, we report the results of a multicenter retrospective French study about efficacy of HMA monotherapy, used frontline or for R/R CBF-AML. Forty-nine patients were included, and received a median of 5 courses of azacitidine (n = 46) or decitabine (n = 3). ORR was 49% for the whole cohort with a median time to response of 112 days. After a median follow-up of 72.3 months, median OS for the total cohort was 10.6 months. In multivariate analysis, hematological relapse of CBF-AML at HMA initiation was significantly associated with a poorer OS (HR: 2.13; 95%CI: 1.04-4.36; p = 0.038). Responders had a significantly improved OS (1-year OS: 75%) compared to non-responders (1-year OS: 15.3%; p < 0.0001). Hematological improvement occurred for respectively 28%, 33% and 48% for patients who were red blood cell or platelet transfusion-dependent, or who experienced grade 3/4 neutropenia at HMA initiation. Adverse events were consistent with the known safety profile of HMA. Our study highlights that HMA is a well-tolerated therapeutic option with moderate clinical activity for R/R CBF-AML and for patients who cannot handle intensive chemotherapy.

Pharmacokinetic Consideration of Venetoclax in Acute Myeloid Leukemia Patients: A Potential Candidate for TDM? A Short Communication.

BACKGROUND: Venetoclax (VNX)-based regimens have demonstrated significantly favorable outcomes in patients with acute myeloid leukemia (AML) and are now becoming the standard treatment. Tyrosine kinase inhibitors are administered at a fixed dose, irrespective of body surface area or weight. For such orally targeted therapies, real-world data have highlighted a larger pharmacokinetic (PK) interindividual variability (IIV) than expected. Even if VNX PKs have been well characterized and described in the literature, only 1 clinical trial-based PK study has been conducted in patients with AML. This study aimed to evaluate the PK of VNX in AML patients. MATERIAL AND METHODS: We retrospectively analyzed all patients treated with a combination of VNX-azacitidine between January and July 2022 at our center, using at least 1 available VNX blood sample. Based on a previously published population PK model, individual PK parameters were estimated to evaluate the exposure and IIV. RESULTS: and Discussion. Twenty patients received VNX in combination with azacitidine, according to the PK data. A total of 93 plasma concentrations were collected. The dose of VNX was 400 mg, except in 7 patients who received concomitant posaconazole (VNX 70 mg). The patients' weight ranged from 49 kg to 108 kg (mean = 78 kg). Mean individual clearance was 13.5 ± 9.4 L/h with mean individual daily area under the concentration-time curves of 35.8 mg.h/L with significant IIV (coefficient of variation = 41.1%). Ten patients were still alive (8 in complete response), but all experienced at least 1 hematological toxicity of grade ≥ 3. CONCLUSIONS: Based on the observed large PK variability in the data from our real-world AML patients, the risk of drug interactions and the recommended fixed-dosage regimen of VNX therapeutic drug monitoring may be useful.

A Markov analysis of azacitidine and venetoclax vs induction chemotherapy for medically fit patients with AML.

ABSTRACT: Although induction chemotherapy (IC) is the standard of care in medically fit patients with newly diagnosed acute myeloid leukemia (AML), limited retrospective data indicate that patients at adverse-risk may benefit from azacytidine and venetoclax (aza-ven). Our goal was to perform a Markov decision analysis to determine whether IC or aza-ven is the optimal induction regimen in this population. Using the TreeAge software, Markov models were created for adverse-risk and intermediate-risk cohorts. A systematic review of the literature informed the transition probabilities and utilities included in the analyses. Our primary outcome was quality-adjusted life years (QALYs) gained over 5 years after diagnosis. Overall, patients at adverse risk treated with IC gained 1.4 QALYs, compared with 2.0 QALYs in patients treated with aza-ven. Patients at adverse risk treated with IC and allogeneic stem cell transplantation (allo-SCT), IC, aza-ven and allo-SCT, or aza-ven gained 2.1, 1.5, 3.0, and 1.9 QALYs, respectively. Meanwhile, patients at intermediate risk treated with IC gained 2.0 QALY, compared with 1.7 QALY in patients treated with aza-ven. Patients at intermediate risk treated with IC and allo-SCT, IC, aza-ven and allo-SCT, and aza-ven gained 2.7, 2.3, 2.6, and 1.8 QALYs, respectively. We have demonstrated that medically fit patients with newly diagnosed adverse-risk AML may benefit from treatment with aza-ven over those treated with IC, whereas IC remains the preferred approach for patients at intermediate risk. Our work challenges the use of the European LeukemiaNet risk classification for patients treated with aza-ven and highlights the need for prospective investigation into aza-ven as induction therapy for medically fit patients.

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML.

ABSTRACT: Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

New treatment opportunities for older patients with acute myeloid leukemia and the increasing importance of frailty assessment - An oncogeriatric perspective.

With the introduction of targeted chemotherapy drugs, a new age of treatment for acute myeloid leukemia (AML) has begun. The promotion of the azacitidine+venetoclax combination regimen to first line of treatment in patients deemed ineligible for intensive chemotherapy marks the first of many novel combination regimens becoming part of national treatment guidelines. We review recent phase II and III clinical trials and conclude that these novel regimens offer significant increases in response rates, remission rates, and overall survival. The incidence of adverse events, the accrued time toxicity, and the healthcare costs, however, are increasing as well. Compared with clinical trials, older patients in the real world frequently present with an inferior baseline health status, which is associated with an increased risk of experiencing side effects. The key to reaping the maximum benefit of the new agents and their combination regimens therefore lies in sufficient attention being given to a patients' preexisting comorbidities, potential frailty, and quality of life. A systematic collaboration between hemato-oncologists and geriatricians can be a potent first step towards addressing the increased treatment intensity patients with AML experience under the novel regimens. In this narrative review article we provide an overview of recent and ongoing clinical trials, highlight encountered adverse events, discuss frailty assessment options, and outline an oncogeriatic care path for older patients with AML.

Female and preserved platelet count subgroups of myelodysplastic syndrome patients benefit from standard-dose azacitidine.

BACKGROUND: Hypomethylating agents, including azacytidine (AZA), are standard therapeutics for patients with high-risk myelodysplastic syndromes (MDS), a group of myeloid neoplasms. However, treatment schedules are not unified in real-world practice; in addition to the standard 7-day (standard-dose) schedule, shortened (reduced-dose) schedules are also used. AIMS: The aim of this study was to discover the patient group(s) which show differential efficacy between standard-and reduced-dose AZA to MDS. METHODS AND RESULTS: The outcome of different AZA doses in a cohort of 151 MDS patients were retrospectively analyzed. Overall survival (OS) was not significantly different between standard- and reduced-dose AZA groups by multivariate analysis. However, an interaction was found between either the sex (female vs. male), the platelet counts (< 40 × 103 /µl vs. ≥ 40 × 103 /µl), or the karyotype risk (< poor vs. ≥ poor) and standard-dose AZA for longer OS. Subgroup analyses revealed better OS with standard- over reduced-dose AZA in female patients (HR, 0.27 [95% CI, 0.090-0.79]; p = 0.011), and those with platelet counts ≥ 40 × 103 /µl (HR, 0.51 [95% CI, 0.26-0.99]; p = 0.041). The union of female and preserved platelet count subgroups also benefited from standard-dose AZA. With this as a test cohort, we next analyzed patients registered in the JALSG MDS212 study, for whom 7-day and 5-day AZA treatment strategies were prospectively compared, as a validation cohort (N = 172). That cohort showed the same tendency as the retrospective results. CONCLUSION: We identified the union of female and preserved platelet count subgroups which benefited from standard-dose AZA, imparting crucial information to physicians planning treatment regimens in MDS patients.

Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Sabatolimab is an immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), an immuno-myeloid regulator expressed on immune cells and leukaemic stem cells. In this trial, we compared the efficacy and safety of sabatolimab plus hypomethylating agent with placebo plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes. METHODS: STIMULUS-MDS1 was a multicentre, randomised, double-blind, placebo-controlled, phase 2 study done at 54 investigational sites in 17 countries. Adult patients (aged ≥18 years) with intermediate-risk, high-risk, and very high-risk myelodysplastic syndromes (according to Revised International Prognostic Scoring System criteria) who had not received previous treatment were included. Patients were randomly assigned (1:1) to intravenous sabatolimab (400 mg on day 8 and 22) or placebo plus a hypomethylating agent (intravenous decitabine 20 mg/m2 on day 1-5 or intravenous or subcutaneous azacitidine 75 mg/m2 on day 1-7 or day 1-5 and day 8 and 9) every 28 days until treatment discontinuation. The two primary endpoints were complete response rate and progression-free survival, assessed in the full analysis set, which included all randomly assigned patients. Complete response was analysed, as prespecified, 7 months after the last patient was randomly assigned. All other analyses presented, including progression-free survival, were done at the final data cutoff prespecified via a protocol amendment on Sept 2, 2021. Safety was assessed in in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03946670, and is ongoing. FINDINGS: Between July 29, 2019, and Aug 10, 2020, 127 patients were randomly assigned to sabatolimab plus a hypomethylating agent group (sabatolimab group; n=65) or placebo plus a hypomethylating agent (placebo group; n=62). The median age of participants was 73 years (IQR 69-77), of whom 86 (68%) of 127 patients were male and 77 (61%) were White. The primary endpoints were not met. Complete response (cutoff date of March 10, 2021) was achieved in 14 (22%; 95% CI 12·3-33·5) of 65 patients in the sabatolimab group vs 11 (18%; 9·2-29·5) of 62 patients in the placebo group (p=0·77). At the cutoff date of the final analysis (March 1, 2022), median follow-up for progression-free survival was 17·8 months (IQR 16·6-19·4) in the sabatolimab group and 19·2 months (17·7-22·3) in the placebo group, and the median progression-free survival was 11·1 months (95% CI 7·6-17·6) in the sabatolimab group vs 8·5 months (6·9-11·3) in the placebo group (hazard ratio 0·75 [95% CI 0·48-1·17]; p=0·1022). The most common adverse events of any grade were neutropenia (35 [56%] of 62 patients in the sabatolimab group vs 43 [68%] of 63 patients in the placebo group), thrombocytopenia (30 [48%] vs 32 [51%]), constipation (29 [47%] vs 24 [38%]), diarrhoea (27 [44%] vs 14 [22%]), anaemia (22 [35%] vs 34 [54%]), febrile neutropenia (22 [35%] vs 15 [24%]), and leukopenia (15 [24%] vs 20 [32%]). One patient developed a serious potential treatment-related immune-mediated adverse event in the sabatolimab group. There was one treatment-related death in the sabatolimab group due to pneumonitis. INTERPRETATION: The addition of sabatolimab to hypomethylating agents in this study did not result in a significant improvement in complete response rates or progression-free survival. Sabatolimab had a manageable safety in most patients with higher-risk myelodysplastic syndromes. A randomised phase 3 trial is ongoing to assess the potential benefit of sabatolimab plus azacitidine on overall survival in this setting. FUNDING: Novartis Pharmaceuticals.

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia.

OBJECTIVES: The combination of Venetoclax (VEN) and Azacitidine (AZA) increases survival outcomes and yields excellent responses in patients with acute myeloid leukemia (AML). However, dose reduction (or discontinuation) is commonly encountered due to therapy-related toxicity. Thus, this study aimed to investigate the efficiency and safety of a lower dosage of venetoclax for the treatment of AML. METHODS: This observational study analyzed the characteristics and outcomes of newly diagnosed AML patients who received 100 mg VEN combined with AZA for 14 days at our institution. RESULTS: A total of 36 patients were enrolled, and the median age at diagnosis was 64 years. After a median follow-up of 15 (range 4-29) months, the median overall survival (OS) and progression-free survival (PFS) for the whole cohort were 17 (4-29) months and 12 (1-28) months, respectively. Meanwhile, the overall response rate (ORR) was 69.4%, and the CRc rate was 66.7% in the whole cohort. Subgroup analysis revealed that NPM1 mutations and FAB-M5 subtype were associated with higher response rates, whereas the adverse ELN risk group was predictive of an inferior response. Moreover, ASXL1, NPM1, and IDH1/2 mutations negatively impacted PFS. DISCUSSION: Our study optimized the administration of venetoclax plus azacytidine for the treatment of AML patients. Response rates were favorable, with median survival in agreement with the findings of earlier reports, offering valuable insights for optimizing VEN-based regimens. CONCLUSION: In summary, the VEN combination regimen is effective for the treatment of newly diagnosed AML patients in the real world despite VEN dose reductions .

Cusatuzumab plus azacitidine in newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy (CULMINATE): part one of a randomised, phase 2, dose optimisation study.

BACKGROUND: Cusatuzumab, a high-affinity anti-CD70 antibody, has shown preliminary activity as a treatment for acute myeloid leukaemia when combined with azacitidine. We aimed to determine the optimum dose for future trials of cusatuzumab in combination with azacitidine in patients with previously untreated acute myeloid leukaemia who are not eligible for intensive chemotherapy. METHODS: In this randomised, phase 2, open-label, dose-optimisation study we enrolled adult patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy, and with Eastern Cooperative Oncology Group scores of 0-2, from 40 hospitals and centres across seven countries. In part one of the trial, participants were randomly allocated 1:1 to 10 mg/kg or 20 mg/kg intravenous cusatuzumab on days 3 and 17, combined with subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles. The primary efficacy outcome was the rate of complete remission in the intention-to-treat group. The two dose cohorts were evaluated independently without between-cohort statistical comparison. Safety analyses were performed in all patients who received one dose of study drug. Part two of the trial was planned to be a single-arm expansion to evaluate cusatuzumab plus azacitidine at the cusatuzumab dose level selected in part one (primary hypothesis ≥35% rate of complete remission vs null hypothesis of 20%); however, changes in the acute myeloid leukaemia treatment landscape during this trial made it unlikely that enrolment to part two of the study would be clinically feasible, so the study stopped at the end of part one. The trial was registered at ClinicalTrials.gov, NCT04023526. FINDINGS: 103 patients were enrolled between Aug 30, 2019, and Feb 25, 2020, and randomly assigned to either cusatuzumab 10 mg/kg (n=51) or 20 mg/kg (n=52). Median follow-up was 7·2 months (IQR 10·7 months). 57 of 103 (55%) patients were male and 46 (45%) patients were female, 78 (76%) were White, one (1%) was Asian, and 24 (23%) did not report their race. In the 10 mg/kg group, complete remission rate was 12% (six of 51 patients; 95% CI 6-23) and in the 20 mg/kg group was 27% (14 of 52; 17-40). Grade 3 or worse treatment-emergent adverse events (TEAEs) were similar between the cusatuzumab 10 mg/kg (n=51) and 20 mg/kg (n=51) cohorts and included thrombocytopenia (24 patients [47%] vs 29 [57%]), anaemia (24 [47%] vs 17 [33%]), and neutropenia (20 [39%] in both cohorts). Serious TEAEs were also similar in the two cohorts (44 [86%] vs 40 [78%]). Treatment-related TEAEs leading to death were reported in both groups (three patients [6%] in the 10 mg/kg group vs one patient [2%] in the 20 mg/kg group); the reported causes of death were pneumonia (n=2) and septic shock (n=2). INTERPRETATION: Although part one of this study was not designed to formally compare the two dose cohorts for efficacy, the totality of clinical data for cusatuzumab studies performed to date indicate that cusatuzumab 20 mg/kg plus azacitidine represents the optimal dose for further studies. A phase 1b study investigating the triple combination of cusatuzumab with venetoclax and azacitidine is underway (NCT04150887). FUNDING: Janssen Research & Development and argenx.

[How did the survival of acute myeloid leukemia change over the last ten years in our unit?] / Hogyan változott az akut myeloid leukaemiás betegek túlélése a terápiás lehetoségek bovülésével az elmúlt 10 évben klinikánkon?

INTRODUCTION: Acute myeloid leukemia (AML) is a hematological malignancy with high mortality rate. The treatment is especially challenging in patients older than 65 years, which is the large majority of those. For patients unfit for intensive chemotherapy regimens, only palliative cytoreduction and basic supportive care used to be the options in our unit. However, from 2018, the azacitidine-venetoclax combination has been a new therapeutic alternative. This treatment resulted in marked survival benefit in clinical trials, however, its impact on the daily clinical practice and the entire patient population is unclear. OBJECTIVE: Our goal was to evaluate how the application of azacitidine-venetoclax changed the treatment and survival of AML patients in our practice. METHOD: We retrospectively analyzed the available clinical data of all AML patients treated consecutively between January 1, 2011 and December 31, 2021 at the 3rd Department of Internal Medicine (from 2020 onward called Department of Internal Medicine and Hematology), examining their treatment depending on the time period of therapy (2011-2017 and 2018-2021). Patients with acute promyelocytic leukemia were excluded. RESULTS: 423 patients were diagnosed during this period. The number of cases showed a marked increase: in the first 7 years of our study, 184 patients were diagnosed, while this rose to 239 during the subsequent 4 years. The median age of patients was 67.6 years, with more than 60% of patients aged over 65. An improving trend can be observed in the overall survival: between 2011 and 2017, the median overall survival was 4.8 ± 0.9 months, while between 2018 and 2021, it was 8.3 ± 1.4 months (p = 0.051). Moreover, in the case of patients over 65 there was a significant overall survival improvement: 3.1 ± 0.5 vs. 4.9 ± 0.6 months (p = 0,01). The main factor behind this improvement could be that a large proportion of over 65 patients previously only fit for supportive care could now be treated with azacitidine-venetoclax: the percentage of actively treated patients grew from 57.1% to 75.3% in the second period. CONCLUSION: The survival of patients unfit for curative therapy and older than 65 showed a steady increase which can be attributed to the introduction of new therapeutic alternatives. Orv Hetil. 2023; 164(45): 1787-1794.

Comparative analysis of hypomethylating agents as maintenance therapy after allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia.

We retrospectively analyzed the outcomes of 136 consecutive patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center. Among them, 76 cases used hypomethylating agents (decitabine, n = 40; azacitidine, n = 36) as post-transplant maintenance therapy, whereas 60 contemporaneous patients did not adopt maintenance therapy. The 3-year incidences of relapse in two groups were 16.6% and 39.2% (p = .001). The 3-year OS and DFS in maintenance group were 84.0% and 78.6%, which were remarkably improved than in control group (60.0% and 58.0%) (p = .004, p = .011). Moreover, the 3-year relapse rates for patients receiving decitabine and azacitidine therapy were 8.5% and 25.0%, respectively (p = .019). Patients utilizing decitabine had more common possibility of grade 3-4 neutropenia than azacitidine (20.0% vs. 2.8%, p = .031). These results indicate that maintenance therapies using hypomethylating agents could reduce the risk of post-transplant recurrence, resulting into remarkable superior survival. Decitabine might lower relapse after allo-HSCT with somewhat more severe myelosuppression when being compared to azacitidine.

Comparative Efficacy of Venetoclax-Based Combination Therapies and Other Therapies in Treatment-Naive Patients With Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy: A Network Meta-Analysis.

OBJECTIVES: This network meta-analysis (NMA) assessed the efficacy of venetoclax (VEN) + azacitidine (AZA) and VEN + low-dose cytarabine (LDAC) compared with AZA, LDAC, and decitabine monotherapies and best supportive care (BSC) in adults with untreated acute myeloid leukemia ineligible for intensive chemotherapy. METHODS: A systematic literature review and feasibility assessment was conducted to select phase III randomized controlled trials for inclusion in the NMA. Complete remission + complete remission with incomplete blood count recovery and overall survival (OS) were compared using a Bayesian fixed-effects NMA. Treatments were ranked using surface under the cumulative ranking curves (SUCRAs) with higher values indicating a higher likelihood of being effective. RESULTS: A total of 1140 patients across 5 trials were included. VEN + LDAC (SUCRA 91.4%) and VEN + AZA (87.5%) were the highest ranked treatments for complete remission + complete remission with incomplete blood count recovery. VEN + LDAC was associated significantly higher response rates versus AZA (odds ratio 5.64), LDAC (6.39), and BSC (23.28). VEN + AZA was also associated significantly higher response rates than AZA (5.06), LDAC (5.74), and BSC (20.68). In terms of OS, VEN + AZA (SUCRA: 95.2%) and VEN + LDAC (75.9%) were the highest ranked treatments. VEN + AZA was associated with significant improvements in OS compared with AZA (hazard ratio 0.66), LDAC (0.57), and BSC (0.37), and VEN + LDAC was associated with significant improvements in OS compared with LDAC (0.70) and BSC (0.46). CONCLUSIONS: VEN + AZA and VEN + LDAC demonstrated improved efficacy compared with alternative therapies among treatment-naive patients with acute myeloid leukemia ineligible for intensive chemotherapy.

Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015).

BACKGROUND: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor. OBJECTIVE: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation. METHODS: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1-7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment. RESULTS: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration-time profiles were similar to observed in adults. The most prevalent grade 3-4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38-100) in MDS and 50% (95% confidence interval 19-100) in JMML. CONCLUSIONS: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML. CLINICAL TRIAL REGISTRATION: EudraCT 2010-022235-10.

Pulmonary infections in patients with acute myeloid leukemia receiving frontline treatment with hypomethylating agents.

Pulmonary infections (PIs) are a major complication of Acute Myeloid Leukemia (AML) treated with hypomethylating agents (HMA). We retrospectively evaluated 147 AML patients treated frontline with HMA in 2 Centers. Total number of HMA cycles was 1397. There were 88 episodes of PI in 64 patients (43.5%). Thirty-five/147 patients at risk (23.8%) developed at least 1 episode of early PI (during cycles 1-2). Median OS in patients who developed early PI was 3.3 months (95% CI 0.8 - 5.8) versus 10.5 months (95% CI 8.4 - 12.7) in patients without PI or with PI beyond the 2nd cycle (p < .001). Early PIs were an independent factor predicting lower survival (OR 1.94, 95% CI 1.28 - 2.93; p = .002). In conclusion, early PIs are common in AML patients receiving HMA and are associated with an unfavorable outcome. The results of our study raise the issue of a tailored infection prevention strategy.