Strong CYP3A4 Research Articles

Elevated Tacrolimus Blood Concentration Due to the Interaction with Nirmatrelvir/Ritonavir During COVID-19 Treatment: A Case Report

Nirmatrelvir/ritonavir, a newly authorized drug for the treatment of COVID-19, is a strong CYP3A4 inhibitor that can interact with many drugs, such as tacrolimus, reducing its metabolism. The reported case is a renal transplant patient who experienced a strong increase in tacrolimus blood concentration (up to 112ng/mL, more than ten times above the target range) when treated with both drugs at the same time, which caused a neurologic condition that required hospital admission for its control and treatment. The resolution of the symptoms was rapid, but the elevation of tacrolimus concentration remained for several days, even after discontinuing both drugs. This case shows the importance of developing a protocol for managing this interaction to guarantee the efficacy and safety of treatment with nirmatrelvir/ritonavir in transplant patients.

Tiered approach to evaluate the CYP3A victim and perpetrator drug-drug interaction potential for vonoprazan using PBPK modeling and clinical data to inform labeling.

Vonoprazan is metabolized extensively through CYP3A and is an in vitro time-dependent inhibitor of CYP3A. A tiered approach was applied to understand the CYP3A victim and perpetrator drug-drug interaction (DDI) potential for vonoprazan. Mechanistic static modeling suggested vonoprazan is a potential clinically relevant CYP3A inhibitor. Thus, a clinical study was conducted to evaluate the impact of vonoprazan on the exposure of oral midazolam, an index substrate for CYP3A. A physiologically-based pharmacokinetic (PBPK) model for vonoprazan was also developed using in vitro data, drug- and system-specific parameters, and clinical data and observations from a [14 C] human absorption, distribution, metabolism, and excretion study. The PBPK model was refined and verified using data from a clinical DDI study with the strong CYP3A inhibitor, clarithromycin, to confirm the fraction metabolized by CYP3A, and the oral midazolam clinical DDI data assessing vonoprazan as a time-dependent inhibitor of CYP3A. The verified PBPK model was applied to simulate the anticipated changes in vonoprazan exposure due to moderate and strong CYP3A inducers (efavirenz and rifampin, respectively). The clinical midazolam DDI study indicated weak inhibition of CYP3A, with a less than twofold increase in midazolam exposure. PBPK simulations projected a 50% to 80% reduction in vonoprazan exposure when administered concomitantly with moderate or strong CYP3A inducers. Based on these results, the vonoprazan label was revised and states that lower doses of sensitive CYP3A substrates with a narrow therapeutic index should be used when administered concomitantly with vonoprazan, and co-administration with moderate and strong CYP3A inducers should be avoided.

Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach

PurposeWe assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose.MethodsIn an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography–tandem mass spectrometry methods.ResultsTherapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37–1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26–1.51), edoxaban to 2.03 (1.84–2.24), and rivaroxaban to 1.44 (1.27–1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001).ConclusionClarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature.Trial RegistrationEudraCT Number: 2018-002490-22

Midostaurin – the First Targeted Therapy Drug for Patients with Acute Myeloid Leukaemia with FLT3 Mutation

The prognosis for patients with acute myeloid leukaemia (AML) varies depending on genetic factors. The presence of mutations in the fms-like tyrosine kinase 3 (FLT3) gene is found in approximately 30% of AML patients. Midostaurin, a first-generation multi-targeted tyrosine kinase inhibitor, is the first FLT3 inhibitor approved for the treatment of newly diagnosed AML patients with the FLT3 mutation in combination with standard induction and consolidation chemotherapy. However, as numerous clinical trials have shown, the list of indications for this drug is likely to be extended. Midostaurin can be administered orally, which improves the patient’s comfort during treatment. In general, it has a favourable safety profile, but interactions with other drugs, such as strong CYP3A4 inhibitors or inducers, which are often used in the concomitant therapy of AML patients, may lead to changes in midostaurin plasma concentrations. In consequence, such interactions may increase the toxicity of the treatment or reduce its therapeutic effect. The aim of this review is to summarise the current knowledge on midostaurin, i.e. its mechanisms of actions, dosage, adverse effects, mechanisms of resistance and limitations to its use. Due to the growing importance of the management of drug-drug interactions mediated via cytochrome CYP3A4, the main focus of this study is the pharmacokinetics of midostaurin and the variability of its plasma concentrations. The Authors emphasise therapeutic drug monitoring with midostaurin as a potential method of managing AML patients with FLT3 mutation.

The pharmacogenetics of the new-generation antipsychotics - A scoping review focused on patients with severe psychiatric disorders.

Exploring the possible correlations between gene variations and the clinical effects of the new-generation antipsychotics is considered essential in the framework of personalized medicine. It is expected that pharmacogenetic data will be useful for increasing the treatment efficacy, tolerability, therapeutic adherence, functional recovery, and quality of life in patients with severe psychiatric disorders (SPD). This scoping review investigated the available evidence about the pharmacokinetics, pharmacodynamics, and pharmacogenetics of five new-generation antipsychotics, i.e., cariprazine, brexpiprazole, aripiprazole, lumateperone, and pimavanserin. Based on the analysis of 25 primary and secondary sources and the review of these agents' summaries of product characteristics, aripiprazole benefits from the most relevant data about the impact of gene variability on its pharmacokinetics and pharmacodynamics, with significant consequences on this antipsychotic's efficacy and tolerability. The determination of the CYP2D6 metabolizer status is important when administering aripiprazole, either as monotherapy or associated with other pharmacological agents. Allelic variability in genes encoding dopamine D2, D3, and serotonin, 5HT2A, 5HT2C receptors, COMT, BDNF, and dopamine transporter DAT1 was also associated with different adverse events or variations in the clinical efficacy of aripiprazole. Brexpiprazole also benefits from specific recommendations regarding the CYP2D6 metabolizer status and the risks of associating this antipsychotic with strong/moderate CYP2D6 or CYP3A4 inhibitors. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommendations about cariprazine refer to possible pharmacokinetic interactions with strong CYP3A4 inhibitors or inducers. Pharmacogenetic data about cariprazine is sparse, and relevant information regarding gene-drug interactions for lumateperone and pimavanserin is yet lacking. In conclusion, more studies are needed to detect the influence of gene variations on the pharmacokinetics and pharmacodynamics of new-generation antipsychotics. This type of research could increase the ability of clinicians to predict favorable responses to specific antipsychotics and to improve the tolerability of the treatment regimen in patients with SPD.

Population Pharmacokinetic and Exposure-Safety Analyses of Ibrutinib for the Treatment of Chronic Graft-Versus-Host Disease.

The population pharmacokinetic (PK) and exposure-response (E-R) analyses for the safety of ibrutinib for the treatment of chronic graft-versus-host disease (cGVHD) is presented. This work aims to develop a population PK model for ibrutinib based on data from clinical studies in subjects with cGVHD, to evaluate the impact of intrinsic and extrinsic factors on PK parameters as well as systemic exposure levels, and to assess an E-R relationship for selected safety end points. Pooled data from 162 subjects with cGVHD enrolled in 4 clinical studies were included in the population PK analysis. In the studies, an ibrutinib dose of 420mg once daily was administered orally. With the exception of 1 study, the study protocols instructed for a reduction of the ibrutinib dose to 140 or 280mg once daily, depending on concomitant CYP3A inhibitor use. Concomitant CYP3A inhibitor use was found to be a primary covariate for relative bioavailability (F1): the F1 value increased 2.22-fold with concomitant moderate CYP3A inhibitors and 3.09-fold with concomitant strong CYP3A inhibitors, compared with the F1 value in the absence of CYP3A inhibitors. In addition, Japanese ethnicity led to an F1 value that was 1.70-fold higher than that in the non-Japanese population. Simulations using the final PK model suggest that ibrutinib exposure was appropriately controlled within the therapeutic range in the entire cGVHD population by applying dose reductions depending on the use of CYP3A inhibitors, and that additional dose modification for the Japanese population would not be required. The subsequent E-R analysis suggests no apparent association between the systemic exposure to ibrutinib and the selected safety end points.

Effect of a strong CYP3A4 inhibitor and inducer on the pharmacokinetics of senaparib (IMP4297) in healthy volunteers: A drug-drug interaction study.

A phase I open-label study assessed the effect of multiple oral doses of a potent CYP3A4 inhibitor (itraconazole) and inducer (rifampicin) on the pharmacokinetic profile of a single oral dose of senaparib, a novel, highly potent poly-(ADP-ribose) polymerase 1/2 inhibitor and CYP3A4 substrate, in Chinese healthy male volunteers (HMV). Adult HMV were enrolled to the itraconazole or rifampicin group (n = 16 each). In Period 1, all participants received a single oral dose of senaparib 40 mg (itraconazole group) or 100 mg (rifampicin group). In Period 2, the same dose was coadministered with itraconazole (200 mg) and rifampicin (600 mg), respectively. The primary endpoints were senaparib exposure parameters. Coadministration with itraconazole significantly increased exposure of senaparib and decreased that of its major metabolites M9 and M14. Maximum plasma senaparib concentration (Cmax ) was increased by ~79% and area under the concentration-time curve (AUC) increased by ~2.8-fold. Coadministration with rifampicin significantly reduced the Cmax and AUC of senaparib by ~59 and 83%, respectively. The Cmax for both M9 and M14 was slightly increased, although AUC was decreased. All treatment-emergent adverse events were grade ≤2, regardless of the treatment administered. In Chinese HMV, the exposure of senaparib was significantly increased when coadministered with itraconazole and significantly decreased when coadministered with rifampicin. It is recommended to avoid concomitant use of senaparib and strong inhibitors or inducers of CYP3A4.

Potential drug-drug interaction of olverembatinib (HQP1351) using physiologically based pharmacokinetic models.

Olverembatinib (HQP1351) is a third-generation BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) (including T315I-mutant disease), exhibits drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4, CYP2C9, CYP2C19, CYP1A2, and CYP2B6. A physiologically-based pharmacokinetic (PBPK) model was constructed based on physicochemical and in vitro parameters, as well as clinical data to predict 1) potential DDIs between olverembatinib and CYP3A4 and CYP2C9 inhibitors or inducers 2), effects of olverembatinib on the exposure of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 substrates, and 3) pharmacokinetics in patients with liver function injury. The PBPK model successfully described observed plasma concentrations of olverembatinib from healthy subjects and patients with CML after a single administration, and predicted olverembatinib exposure increases when co-administered with itraconazole (strong CYP3A4 inhibitor) and decreases with rifampicin (strong CYP3A4 inducer), which were validated by observed data. The predicted results suggest that 1) strong, moderate, and mild CYP3A4 inhibitors (which have some overlap with CYP2C9 inhibitors) may increase olverembatinib exposure by approximately 2.39-, 1.80- to 2.39-, and 1.08-fold, respectively; strong, and moderate CYP3A4 inducers may decrease olverembatinib exposure by approximately 0.29-, and 0.35- to 0.56-fold, respectively 2); olverembatinib, as a "perpetrator," would have no or limited impact on CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activity 3); systemic exposure of olverembatinib in liver function injury with Child-Pugh A, B, C may increase by 1.22-, 1.79-, and 2.13-fold, respectively. These simulations inform DDI risk for olverembatinib as either a "victim" or "perpetrator".

A phase 1, open-label, randomized drug–drug interaction study of zanubrutinib with moderate or strong CYP3A inhibitors in patients with B-cell malignancies

BTK inhibitor exposure increases significantly when coadministered with CYP3A inhibitors, which may lead to dose-related toxicities. This study explored the pharmacokinetics, efficacy, and safety of zanubrutinib when coadministered with moderate or strong CYP3A inhibitors in 26 patients with relapsed or refractory B-cell malignancies. Coadministration of zanubrutinib (80 mg BID) with moderate CYP3A inhibitors fluconazole and diltiazem or zanubrutinib (80 mg QD) with strong CYP3A inhibitor voriconazole resulted in comparable exposures to zanubrutinib (320 mg QD) with AUC0-24h geometric least squares mean ratios approaching 1 (0.94, 0.81, and 0.83, for fluconazole, diltiazem, and voriconazole, respectively). The most common treatment-emergent adverse events were contusion (26.9%), back pain (19.2%), constipation and neutropenia (15.4% each), and rash, diarrhea, and fall (11.5% each). This study supports current United States Prescribing Information dose recommendations for the coadministration of reduced-dose zanubrutinib with moderate or strong CYP3A inhibitors and confirms the favorable efficacy and safety profile of zanubrutinib.

Effects of a ritonavir-containing regimen on the pharmacokinetics of sirolimus or everolimus in healthy adult subjects.

The immunosuppressive agents sirolimus and everolimus are sensitive CYP3A4 substrates with narrow therapeutic index. Ritonavir is a strong CYP3A inhibitor. A phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of the co-administration of sirolimus or everolimus with the ritonavir-containing 3D regimen of the direct-acting antiviral agents ombitasvir, ritonavir-boosted paritaprevir, and dasabuvir in healthy subjects. This study had two independent arms, each with a two-period, single-sequence, crossover study design. A single dose of sirolimus 2mg (N=12) or everolimus 0.75 mg (N=12) was administered in Period 1. In Period 2, multiple doses of the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily and dasabuvir 250 mg twice daily) were administered for 34 or 28 days, with a single dose of sirolimus 0.5mg or everolimus 0.75 mg co-administered on Day 15. Following co-administration with the 3D regimen, the sirolimus dose-normalized maximum observed blood concentration (Cmax ) and area under the blood concentration-time curve from time zero to infinity (AUCinf ) increased to 6.4-fold and 38-fold, respectively. Following co-administration with the 3D regimen, the everolimus Cmax and AUCinf increased to 4.7-fold and 27-fold, respectively. Sirolimus and everolimus half-lives increased from 96 to 249 h, and 42 to 118 h, respectively. There were no major safety or tolerability issues in this study. The ritonavir-containing 3D regimen resulted in a significant increase in sirolimus or everolimus exposure, consistent with the known strong inhibitory effect of ritonavir on CYP3A requiring dose and/or frequency modification when co-administered with each other.

A Physiologically-Based Pharmacokinetic Model of Ruxolitinib and Posaconazole to Predict CYP3A4-Mediated Drug-Drug Interaction Frequently Observed in Graft versus Host Disease Patients.

Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug-drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim® Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (Cmax) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.

P079Etonogestrel contraceptive implant users can experience breakthrough ovulation with only two weeks of exposure to a strong cyp3a inducer

<h3>Objectives</h3> Rifampin is a strong CYP3A inducer and the gold standard for evaluating CYP3A-mediated drug-drug interactions per the US Food and Drug Administration. We hypothesized that even a short course (two weeks) of exposure would lead to breakthrough ovulation-mediated changes in endogenous estradiol (E2) and progesterone (P4) concentrations among etonogestrel (ENG) implant users. <h3>Methods</h3> We enrolled healthy people using ENG implants for 12–36 months. We measured baseline serum concentrations of E2 and P4 as surrogate biomarkers for ovulation suppression using clinical chemiluminescent immunoassays. After two weeks of rifampin 600 mg daily, we repeated E2 and P4 measurements. We determined breakthrough ovulation based on pre-exposure P4 3.0ng/mL with concurrent rise in post-treatment E2. <h3>Results</h3> Fifteen participants completed all study procedures. Participants' median age was 28.2 (range, 21.8–34.1), median BMI was 25.2 kg/m2 (range, 18.9–37.3), and median duration of implant use was 22 months (range, 12–32). At baseline, median E2 concentrations were 73 pg/mL (range, 32–686) and median P4 concentrations were 0.3 ng/mL (range, 0.2–6.1). After concomitant rifampin, median E2 concentrations were 201 pg/mL (range, 59–951) and median P4 concentrations were 0.4 ng/mL (range, 0.2–15.8). Serum E2 concentrations significantly increased with rifampin exposure (p=0.003, paired Wilcoxon signed rank test), but the increases in serum P4 concentrations were not statistically significant (p=0.185). Three participants (20%) experienced breakthrough ovulation with the following P4 changes: 0.3>5.0, 0.8>7.3, 0.5>15.8 (pre>post; ng/mL). <h3>Conclusions</h3> With only a short exposure to a strong CYP3A inducer, ENG implant users experienced clinically significant changes in hormone biomarkers indicative of waning follicular development and ovulation suppression.

Antifungal Choice during Intravenous to Oral Cyclosporine Switch Effects Bioavailability in Patients Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Cyclosporine is a key drug during hematopoietic stem cell transplantation for the prevention of Graft-versus-Host disease with the potential for involvement in drug-drug interactions. We conducted this study to evaluate the effects of antifungals on cyclosporine blood levels and biavailability values. Material and Methods: Patients who had allogeneic hematopoietic stem cell transplantation with normal kidney and liver function and no other drug-drug interactions that could affect cyclosporine blood levels were included in the study. Patients were categorized into moderate (fluconazole) and strong (voriconazole, posaconazole) CYP3A4 inhibitor antifungal users and non-azole (amphotericin B, caspofungin) users. We collected intravenous and oral cyclosporine blood concentrations and doses during cyclosporine administration route changes and evaluated the effects of them according to antifungal groups. Results: We included 94 patients. The moderate and strong CYP3A4 inhibitor user numbers were 54 and 22, respectively. 18 patients with non-azole antifungal prescriptions were included. ANOVA revealed that there was a statistically significant difference in blood corrected concentrations (p<0.0001). The mean oral dose to intravenous dose ratio was 1.44 and 1.53 for the strong and moderate CYP3A4 inhibitor groups, respectively. This ratio was 1.51 for non-azole antifungal users. The median cyclosporine concentrations were higher after switching to oral cyclosporine in three antifungal groups. The highest mean cyclosporine concentration was 378,45 ng/mL and was obtained from patients with strong CYP3A4 inhibitor antifungals. The lowest mean cyclosporine concentration was observed in patients who were prescribed non-azole antifungals, which was subtherapeutic at 165,95 ng/mL. Bioavailability values were 1.17, 0.97, and 0.9 for moderate inhibitor, strong inhibitor, and non-azole users, respectively. In our study, the general oral dose to intravenous dose ratio regardless of the antifungal choice was 1.50. Despite having the lowest dose ratio (1.44), the highest bioavailability (1.17) was achieved by strong CYP3A4 inhibitor users, and nine of them experienced supratherapeutic cyclosporine levels. After applying a 1.53 dose ratio, the highest mean dose ratio among groups, the number of patients with supratherapeutic cylosporine levels increased to twenty-two from six. Eight patients with non-azole antifungal prescriptions still experienced subtherapeutic cyclosporine blood levels after the initiation of a 1.51 mean dose ratio, which suggests non-azole users may need higher oral cyclosporine doses (Figure 1). Conclusion: Cyclosporine is a gold medicine during the allogeneic hematopoeitic stem cell trasnplantation process. Concomitant antifungal therapy affects cyclosporine blood levels during cyclosporine administration.Patients who are prescribed non-azole antifungals such as caspofungin and amphotericin B are at an increased risk of Graft-versus-Host disease due to the lack of therapeutic cyclosporine levels. Patients with azole antifungals may face cyclosporine toxicities during cyclosporine route change due to hepatic enzyme inhibitions. For patients with strong CYP3A4 inhibitor antifungals such as voriconazole and posaconazole, the oral dose to intravenous dose ratio should be adjusted carefully to avoid toxicity. Fluconazole, a moderate CYP3A4 inhibitor, causes a wide range of cyclosporine blood levels, which makes it hard to advise strict dose ratios. Because patient responses to enzyme inhibitors varied in our study, we advise taking precautions on an individual basis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Population Pharmacokinetics and Exposure-Response Analyses from Phase I-III Studies Support Copanlisib Dose Selection in Relapsed Indolent Non-Hodgkin Lymphoma

Introduction: Copanlisib is a novel PI3K inhibitor that is approved for single-agent treatment of relapsed follicular lymphoma in patients (pts) who have received ≥2 systemic therapies. In the pivotal Phase III CHRONOS-3 study, pts with relapsed iNHL were randomized to copanlisib at the approved maximum tolerated dosing regimen of 60 mg administered on days 1, 8, and 15 of a 28-day cycle in combination with standard rituximab (C+R) or placebo plus rituximab (P+R) and demonstrated superior progression-free survival (PFS) of C+R vs P+R (hazard ratio [HR]: 0.52; Matasar et al. Lancet Oncol 2021). In an updated 1-year follow-up analysis, the benefit of C+R was confirmed in the overall relapsed iNHL population (Zinzani et al. EHA 2022). No dedicated dose-finding studies have been undertaken to investigate copanlisib dose selection when used in combination with rituximab; however, initial safety assessments demonstrated acceptable tolerability. We investigated popPK and ER relationships for copanlisib efficacy and safety from a pooled analysis, with particular focus on the 1-year follow-up of CHRONOS-3 to confirm copanlisib dose selection. Methods: A copanlisib comprehensive popPK model was developed from 712 pts across 9 copanlisib clinical Phase I-III studies. Demographic, laboratory, and co-medication covariates were investigated for their influence on copanlisib between-patient PK variability. Individual static and time-varying exposure estimates for pts enrolled in CHRONOS-3 were derived to investigate relationships to efficacy (PFS) and key treatment-emergent safety events using Cox proportional hazards (CPH) and multivariate logistic regression analyses after accounting for predefined potentially prognostic demographic, laboratory, and/or disease-related baseline covariates. Results: Copanlisib PK was best described by a 3-compartment PK model with first-order elimination following intravenous infusion. Copanlisib PK was dose proportional and time independent, with no accumulation with the approved dosing regimen. Statistically selected covariates influencing copanlisib PK included rifampin (strong CYP3A inducer) and itraconazole (strong CYP3A inhibitor) co-administration and mild or worse hepatic impairment, confirming the results of dedicated clinical pharmacology studies. Additional covariates influencing copanlisib PK included female sex, residence in Japan, and a CHRONOS-3 study effect, with the majority of covariates or subpopulations defined by sex, age, body weight, renal function, and geographic region showing exposure variations not exceeding traditional bioequivalence ranges (80-125%). In CHRONOS-3, CPH analyses demonstrated a statistically significant, positive ER relationship for PFS for all 3 time-varying copanlisib exposure estimates (average concentration [Cavg] over 2 weeks [Cavg2wk]: p=0.002; 4 weeks [Cavg4wk]: p=0.004; and 8 weeks [Cavg8wk]: p=0.002), along with a near-significant relationship for area under the curve from 0 to 168 hours (AUC(0-168)nd) [p=0.023] (Figure 1). Therefore, greater copanlisib exposure was associated with prolonged PFS, while lower copanlisib doses may result in reduced efficacy in relapsed iNHL. CPH and/or logistic regression analyses demonstrated no significant ER relationship for investigated safety events (serious adverse events [AEs], grade ≥3 treatment-emergent AEs, hyperglycemia, hypertension, diarrhea, nausea, fatigue, lung infections, and neutropenia of any grade). Thus, lower starting doses of copanlisib are not anticipated to improve safety and tolerability. ER analyses support the overall positive benefit/risk assessment of copanlisib reported from the clinical efficacy and results of CHRONOS-3 in iNHL. Conclusion: PopPK and ER analyses substantiate administration of a dosing regimen of copanlisib 60 mg on days 1, 8, and 15 of a 28-day cycle in the relapsed iNHL population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax-Based Salvage Therapy Improves Outcome in Relapsed/Refractory AML Patients Eligible for Intensive Treatment: A Propensity Score Matching Analysis

Background: Venetoclax (VEN)-based combination therapy with hypomethylating agents (HMA) has been approved for first-line treatment in AML patients ineligible for intensive treatment. There is evidence for efficacy also in the in relapsed/ refractory setting (R/R) in fit patients pretreated with intensive regimes, but comparative controlled data is lacking. Here, we report our updated data of VEN-based salvage treatment as bridge to allogeneic hematopoietic cell transplantation (allo-HCT) in R/R AML patients and compared it to non-VEN-based intensive treatment according to physician's choice in a propensity score matching analysis using patient data from the German Study Alliance Leukemia (SAL) registry (ClinicalTrials.gov Identifier: NCT03188874). Design/Methods: We analyzed patients with R/R AML after initial intensive induction therapy, who started VEN-based salvage treatment as bridging to allo-HCT at the University Hospital Heidelberg between October 2018 and April 2021. Using propensity score matching, these patients were compared to patients from the registry of the SAL, who received non-VEN-containing salvage treatment based to the decision of the treating physician. Results: A total of 37 patients (median age 62 y, range 23 to 79 y), who received VEN-based salvage treatment were included. All patients had initially received intensive therapy, 25 patients (68 %) had been refractory to an intensive induction therapy regime, 12 patients (32 %) had been diagnosed with morphologic (9 patients) or molecular relapse (3 patients) after intensive first line therapy. According to the 2017 ELN classification, 10 patients (27%) had favorable risk, 10 (27%) intermediate risk and 17 (46%) adverse risk disease. 36 patients received VEN in combination with standard-dose azacytidine and one patient with low-dose cytarabine. VEN was given at a daily dose of 400mg/day in 21 to 28 days cycles after initial ramp up or at a reduced dose of 100mg/day in case of co-medication with strong CYP3A inhibitors. The overall response rate (CR, CRi, MLFS and PR) in VEN-based treated patients was 89% (n=33) with CR/CRi being the best response in 57% (n=21), MLFS in 19% (n=7) and PR in 13% (n=5) of the patients. 30- and 60-day mortality was 3% (n=1). Eventually, allo-HCT was performed in 26 patients (70%). At the time of analysis 17 (65%) of these patients were alive and 16 (62%) were still in CR. For comparison, we identified 88 patients (median age 61 y; range 22- 78 y) within the SAL-registry, who received an intensive non VEN-containing salvage therapy for their R/R AML. The SAL cohort contained more patients with intermediate risk (ELN 2017 classification) than the VEN-treated cohort (56% vs. 27%; p=0.005) but less patients with adverse risk (22% vs. 46%; p=0.009). The distribution of favorable risk was similar (23% vs. 27%; p=0.65). Allo-HCT was performed in 59 patients (67%) and in 31 patients allo-HCT was the first salvage treatment after relapse (n=10) or refractoriness to induction therapy (n=21). The remission status prior to allo-HCT was CR/CRi in 11 (19%), PR in 7 (12%), progressive disease (PD) in 38 (64%) and unknown in 3 patients (5%). After a median follow-up of 18.1 months (95%-confidence interval (CI) 13.0-24.4) for the VEN-treated cohort and 56.2 months (95%-CI 24.3-84.9) for the SAL cohort, the median event-free survival (EFS) and relapse-free survival (RFS) of VEN-treated patients were 8.02 months (95%-CI, 5.06-not reached [NR]) and 7.16 months (95%-CI, 4.37-NR), respectively. In contrast, median EFS and RFS for the SAL cohort were 4.53 months (95%-CI, 3.45-8.51) and 9.66 months (95%-CI, 5.59-20.6), respectively. Median overall-survival (OS) in the VEN-cohort was 15.08 months (95%-CI, 10.55-NR) compared to 9.66 months (95%-CI, 4.99-19.5) in the SAL cohort. Propensity score matching including age, white cell count, sex and ELN-risk and allo-HCT status as matching variables revealed a non-significant (p=0.148) benefit for the VEN-treated cohort with a hazard ratio of 0.65 (95%-CI, 0.36-1.17) compared to the SAL cohort. In patients proceeding to allo-HCT, 18-month survival was 60% (95%-CI, 42-85%) compared to 51% (95%-CI, 40-66%) in the SAL cohort. Conclusion: Our data confirms that VEN-containing therapy is a safe and effective salvage therapy for patients with R/R AML that allows an efficient bridging to allo-HCT in many patients with promising outcome after allo-HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Pilot Study Evaluating Acalabrutinib for the Treatment of Relapsed/Refractory Primary and Secondary Central Nervous System Lymphomas

Background: Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes, and/or spinal cord without evidence of systemic disease. While frontline PCNSL is potentially curable, relapsed PCNSL has a dismal prognosis, particularly if the relapse is within 1 year of frontline therapy. Secondary central nervous system lymphoma (SCNSL) is defined as systemic NHL that has CNS involvement either concurrently or at relapse. There is no standard of care for relapsed CNS lymphoma. Recently, though, novel targeted agents have shown promise. Bruton's tyrosine kinase (BTK) is a key enzyme in the B-cell receptor (BCR) signaling pathway. In some B-cell NHL, BTK is essential for proliferation and survival. The BTK inhibitor (BTKi) ibrutinib is effective for the treatment of both primary and secondary CNS lymphomas with response rates of 68% (CR=45%) and 56% (CR=17%), respectively. Acalabrutinib is an irreversible BTKi that has been evaluated in NHL. Phase 2 trials of acalabrutinib in relapsed/refractory MCL reported an ORR of 80.6% with a CR rate of 39.5%. Importantly, there were no cases of atrial fibrillation and only 1 case of grade 3 or higher gastrointestinal hemorrhage. We hypothesize that acalabrutinib, a more selective BTKi, may be an effective treatment for relapsed CNS lymphomas with fewer complications. Study Design/Methods: This is a multicenter, open-label, single-arm, pilot study designed to investigate the antitumor effects of acalabrutinib in subjects with relapsed PCNSL or SCNSL that is open to accrual (NCT04548648). All subjects receive acalabrutinib 100mg every 12 hours until progression or discontinuation of treatment due to an adverse event. Prophylactic administration of the antifungal agent isavuconazole will be mandatory while subjects receive acalabrutinib. This decision is based on cases of invasive aspergillosis in studies evaluating ibrutinib. As a moderate CYP3A4 inhibitor, isavuconazole may increase acalabrutinib levels. Pharmacokinetic studies have shown that coadministration may increase acalabrutinib dosing 2- to 3-fold. We feel that this possible increase in concentration is reasonable given the need for blood-brain-barrier penetration. During the study, 15 evaluable subjects will be enrolled and treated. Response will be assessed via brain magnetic resonance imaging (MRI) after 2, 4, 6, 9, 12, 18 and 24 months. After 24 months, patients will require yearly MRIs for response assessment. The primary endpoint is overall response rate (ORR) at 2 months of therapy. Secondary endpoints include toxicity, complete response (CR) rate, progression free survival (PFS), duration of response (DoR), and overall survival (OS). Key inclusion criteria include: biopsy (can be from initial diagnosis) or MRI findings consistent with B-cell NHL in CNS; ocular and CSF involvement are allowed but there must be a parenchymal mass as well; at least one prior line of therapy; no systemic involvement; ECOG performance status < 2. Key exclusion criteria include: previous BTKi exposure; anticoagulation with warfarin; strong CYP3A4 inhibitor that cannot be stopped; severe hepatic insufficiency; inability to take oral medication. Correlative studies include blood and CSF pharmacokinetic studies of acalabrutinib and its active metabolite, ACP-5862 (collected on day 1 and 8 of cycle 1). Molecular testing will be performed on biopsy samples to evaluate the presence of mutations in the MYD88 and CXCR4 genes. Additionally, the utility of 82Rubidium as a positron emission tomography-radiotracer will be evaluated (at screening and prior to cycle 3 and cycle 7) in the first five subjects at the University of North Carolina who consent to this scan. Mental status and cognitive function will be evaluated with the mini-mental status examination (MMSE) at screening then every 6 months. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Chemo-Free Bridge-to-Transplant Strategy with Venetoclax and Azacitidine for NPM1-Mutated Acute Myeloid Leukemia in Molecular Failure

Background: In patients (pts) with NPM1-mutated acute myeloid leukemia (AML) fit for intensive chemotherapy, the persistence, reoccurrence, or progression of NPM1mut transcript identifies poor chemotherapy responders that require allocation to allogeneic stem cell transplantation (alloSCT). Currently, there is no standard of care for pts in molecular failure and the proper bridging strategy to alloSCT still needs to be defined. The combination of Venetoclax (VEN) and Azacitidine (AZA) offers an alternative chemo-free strategy with favorable toxicity profile in NPM1mut AML, a molecular subset exquisitely sensitive to VEN. Aims: To characterize a series of NPM1mut AML pts in molecular failure who received VEN-AZA as bridge-to-transplant treatment strategy. Methods: We explored the off-label combination of Venetoclax (VEN) and Azacitidine (AZA) in 9 NPM1mut fit AML pts in molecular failure after intensive chemotherapy eligible for alloSCT, treated at 4 Italian Hematology Institutions. Disease was monitored on bone marrow (BM) with NPM1mut-specific qRT-PCR assay. The quantitative detection limit of the assays was 0.01%. Complete response with minimal residual disease negativity (CR-MRDneg) was defined as ratio NPM1mut/ABL x 100 transcript < 0.01 copies Results: Of the 9 pts analyzed 4 (44%) were female, median age at diagnosis was 56 years (range 41-66) and 58 years (range 43-68) at VEN-AZA therapy. Eight of the 9 pts had ELN2017 favorable-risk AML (2 pts with concomitant FLT3-ITDlow and 1 FLT3-TKD) and 1 pt had intermediate-risk AML (FLT3-ITDhigh). Pts received in median 4 (range 2-5) cycles of front line chemotherapy. Seven pts were treated for molecular relapse and 2 for molecular persistence/progression. All pts received full VEN dosage (400 mg/die or 100 mg/die if concomitant strong CYP3A4 inhibitor) and AZA 75 mg/m2/die s.c. in 5- or 7-day schedule. All pts but 1 performed VEN ramp-up. Pts received a median of 3 cycles (range 1-4). No AZA dose reduction occurred. Median VEN duration during cycle (C)1 was 25 days (range 14-28), 21 days (range 7-28) in C2, 24.5 days (range 7-28) in C3 and 25.5 days (range 19-28) in C4. VEN dosage reductions were due to hematological toxicity ≥ G3 in 60% of cases and in 40% for logistic reasons. The observed ≥ G3 toxicities were neutropenia in 4/9 (44%) pts, 1 thrombocytopenia and 1 febrile neutropenia, managed out-patient. No tumor lysis syndrome was observed. Best response to VEN-AZA was CR MRDneg (NPM1mut undetectable) in 7/9 (78%) pts, reached after a median of 2 cycles (range 1-4). Importantly, no pts relapsed ongoing therapy; 1 pt, notably the FLT3-ITDhigh pt, in CR MRDpos presented molecular progression after C3. Median time from VEN-AZA start to alloSCT was 4.3 months (range 1.7-8.1). At pre-transplant evaluation 6/9 (67%) pts were in CR MRDneg. Eight of 9 pts received myeloablative conditioning and 1 pt received reduced-intensity conditioning. With a median follow-up from alloSCT of 9.3 months (range 2.4-24.0) all patients are alive and 8/9 (89%) in CR MRDneg. Four pts presented NPM1mut reoccurrence after alloSCT: in 2 pts CsA tapering achieved molecular negativity, 1 pt underwent prophylactic therapy with sorafenib and 1pt is currently in CR MRDpos. In no pts FLT3 mutations were detected and, most importantly, no patients experienced morphological relapse. Conclusions: VEN-AZA demonstrated to be a safe and effective bridging regimen for NPM1mut AML pts in molecular failure, allowing to achieve deep responses in the majority of pts at the expense of low toxicity. These preliminary encouraging results will be explored in the GIMEMA AML2521 trial in the same patient subset (clinicaltrials.gov NCT04867928).

Itacitinib and Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease: Phase 1/2 Results from Gravitas-309

Background: Itacitinib is a potent, selective oral Janus kinase (JAK) 1 inhibitor with broad anti-inflammatory activity. GRAVITAS-309 was designed as a 2-part, multicenter, randomized trial to assess the efficacy and safety of itacitinib in combination with corticosteroids (CS) as first-line treatment for moderate or severe chronic graft-versus-host disease (GVHD). We describe preliminary results from the open-label, dose-finding portion of the study. Methods: The study initially investigated itacitinib at doses of 200 mg once daily (qd; n=11) and 300 mg qd (n=10) in combination with CS. Both doses were well tolerated. The trial was then expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300-mg qd cohort was expanded, and a CS monotherapy cohort was added (Figure 1). The expected CS starting dose was 0.5-1 mg/kg per day prednisone (or methylprednisolone equivalent) with a dose taper initiated on Day 14 or earlier during the second week of treatment and following published recommendations (Flowers and Martin. Blood. 2015;125[4]:606-15). Itacitinib dosage was initially reduced by 100 mg when given concomitantly with a strong CYP3A4 inhibitor (sCYP3A4i; eg, azole antifungals). A total of 140 patients (pts) (35/treatment group) with moderate or severe chronic GVHD were to be randomized 1:1 using chronic GVHD risk status (moderate vs severe) as a stratification factor. The primary objective was to identify the appropriate dose and schedule of itacitinib for further development. The data cutoff was January 31, 2022. Results: 103 pts were enrolled and received at least one dose of itacitinib. The cohorts were well balanced for pt and disease characteristics. Median age was 57 years (range, 23-76) for the itacitinib cohorts and 59 years (range, 28-75) for the CS cohort. Approximately two-thirds of pts had moderate chronic GVHD. At the time of data cut, 39 (38%) pts in the itacitinib cohorts and 10 (28%) pts in the CS cohort continued study treatment. Median duration of study treatment was 27-28 weeks for the itacitinib cohorts (including 13-16 weeks of concomitant CS) and 17 weeks for the CS cohort. The itacitinib 300-mg bid dose cohort was discontinued early due to malignancy relapse occurring in 4/29 (14%) pts and more pts requiring dose reductions compared with the 400-mg qd and 300-mg qd cohorts (28% vs 17% and 8%, respectively), mostly due to cytopenias. Incidence of grade ≥3 treatment-emergent adverse events (AEs) was higher in the itacitinib cohorts than with CS (65% vs 31%) and were reported most commonly in the system organ classes of infections (44% vs 6%) and blood and lymphatic system disorders (23%-34% vs 6%). Cytomegalovirus (CMV) infections occurred in 10%-15% of pts in itacitinib cohorts (including CMV pneumonia [n=3], esophagitis [n=1], enteritis [n=1]) vs 3% with CS. The all-cause mortality rate was 14%-18% in itacitinib cohorts vs 11% with CS, with infections the leading cause. The overall response rate (ORR) at 6 months was 46% (complete response [CR], 14%) with 300-mg qd and 53% (CR, 32%) with 400-mg qd, vs 36% (CR, 18%) with CS. A preliminary exposure-response analysis showed a bell-shaped curve with maximum efficacy decreasing at higher exposures, consistent with increasing incidence of AEs. 60%-70% of patients received coadministration with a sCYP3A4i at any time point during study treatment, which increased itacitinib exposure across all doses, requiring dose reduction by 200 mg qd. Conclusion: Preliminary results for first-line treatment of moderate or severe chronic GVHD showed an increase in ORR and CR rate with itacitinib + CS vs CS alone in both the 300-mg qd and 400-mg qd cohorts, at the expense of increased rates of cytopenias, infections, and mortality. This benefit:risk ratio does not support moving the combination of itacitinib + CS to a later phase of development in first-line therapy of chronic GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Response and Prolonged Treatment-Free Remission after a Short-Course of Modified Intensive Chemotherapy and Venetoclax in Elderly AML: An Updated Analysis of the Caveat Trial

Background Venetoclax (VEN) plus azacitidine has an established role in the management of older patients (pts) with AML (DiNardo, NEJM 2020). To explore the feasibility of intensive chemotherapy combined with VEN in older pts with newly diagnosed AML, we conducted the CAVEAT trial (Chua et al, JCO 2020). We now present an updated analysis of this trial (with >3 years median follow-up), reporting on the optimal dose of VEN with chemotherapy, with and without posaconazole (POSA), the deliverability of consolidation therapy, characteristics of treatment failure and observation of substantial treatment-free remission in subsets of pts using this time-limited, short-course regimen. Methods The CAVEAT study enrolled pts aged ≥65 years with de novo or secondary/therapy-related AML (sAML) considered suitable for intensive chemotherapy. Five VEN dose escalation cohorts (50-100-200-400-600 mg) were explored initially. Two additional cohorts examined the safety of adjusted dosing of VEN (50 or 100 mg) during anti-fungal prophylaxis with the strong CYP3A4 inhibitor POSA. For induction, VEN was administered over 14 days, commencing with a 7-day pre-chemo dose ramp-up, followed by a 7-day overlap with 5+2 chemotherapy (cytarabine 100mg/m2/d IVI d1-5 and idarubicin 12mg/m2 IV d2-3). Consolidation (CONS) with 2+1 chemotherapy (below), followed by up to 7 cycles of VEN monotherapy maintenance was planned. Results Data cut-off: 31MAR2022. A total of 69 pts are included in this analysis (first pt 17JUL2016, last pt 15MAY2020). Median age was 71 years (range 63-80). Poor risk features included sAML (42%), adverse karyotype (28%) and prior HMA (23%). From the dose escalation phase, the VEN 600 mg cohort was well tolerated (30-day mortality 6%). Induction with VEN-POSA (n=18) was also well tolerated (30-day mortality 0%) with 3 DLTs observed: 2 hematologic (1 in each cohort) and 1 due to pulmonary infiltrates occurring on d2 induction (suspected to be allopurinol hypersensitivity). No clinical TLS was observed. Although hematologic recovery was satisfactory after VEN-POSA induction, recovery was considerably longer in the VEN (100mg)-POSA cohort after CONS1 compared to VEN (50mg)-POSA for both neutrophils (median 64 vs 44d to 0.5 x109/L) and platelets (median not reached vs 26d to 50 x109/L). Therefore, if POSA is used concurrently, VEN 50 mg is recommended. Alternatively, if VEN 600 mg is used, POSA should commence only after completion of VEN. In the VEN 600 mg cohort, significant delays in hematological recovery were also observed after multiple rounds of attenuated CONS (VEN d1-14, bolus doses of cytarabine 100 mg/m2 d1-2, idarubicin 12 mg/m2 on d1), limiting deliverability (median CONS cycles 1; range 1-3). By intention-to-treat, the overall response (CR/CRi) rate was 73%. CR/CRi was 90% in de novo AML (vs 51% in sAML), 84% in intermediate karyotype (vs 69% in adverse), 76% and 83% in NPM1 and IDH2 mutant AML, respectively. With a median follow-up of 37 months (m), the median overall survival (OS) was 15.4m. Median OS was 31.3m in de novo AML (40% alive at 36m) and 30.3m in intermediate karyotype AML (38% alive at 36m). In the VEN 600 mg cohort, median OS was 24.1m (36% alive at 36m). As CAVEAT delivered just one intensive cycle of therapy, followed by limited post remission therapy (median time on therapy 7.7m), we next assessed the duration of treatment-free remission (TFR) among responders. Among pts achieving CR/CRi, 20/51 (39%) experienced TFR (Fig 1). The median TFR was 22.1m (range 4.6-48.3m). At data cut-off, 12 (24%) have ongoing TFR. Notably, 15/20 (75%) with TFR had an NPM1 or IDH2 mutation at diagnosis. 11 out of 14 evaluable pts with NPM1 mutation had mutation clearance by RT-qPCR, including 3 with NPM1 negative disease at time of failure (1 refractory, 2 relapse). Two pts with persistently mutated NPM1 at relapse had a concomitant FLT3-ITD or KIT mutation. The mutation landscape at relapse is shown (Fig 1) Conclusion VEN combined with modified intensive chemotherapy achieved high response rates in older pts with newly diagnosed AML. With long-term follow-up, the time-limited CAVEAT schedule enabled pts, especially with mutated NPM1 or IDH2, to experience a durable treatment-free remission. Cumulative hematological toxicity is limiting, prompting us to now explore non-anthracycline CONS (low dose cytarabine 20mg/m2 SC d1-10 + VEN 400mg d1-7, for up to 4 cycles), followed by VEN monotherapy (400mg D1-14 q28d cycle x7). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Q-TWiST in Venetoclax-Based Regimens in Elderly Patients with AML: A Quality-Adjusted Analysis

Introduction: Non-intensive venetoclax-based regimens are the current standard of treatment for acute myeloid leukemia (AML) in the elderly. Phase 3 VIALE-C (LDAC vs. LDAC+Ven) and VIALE-A (Aza vs. Aza+Ven) trials showed improved median overall survival (OS) from 4.1 to 7.2 months (VIALE-C) and from 9.6 to 14.7 months (VIALE-A), with serious adverse events (SAEs) in 73% low-dose AraC (LDAC), 83% (Aza + Ven), 66% (LDAC + Ven). Quality of the time gained with these regimens is particularly important in this population. Q-TWiST is a useful tool to adjust the OS to quality time without symptoms or toxicity. This kind of analysis has been previously published in newly diagnosed AML in glasdegib + LDAC vs LDAC trials (Solem CT, 2020), and in the CPX-352 vs 7+3 (Cortes JE, 2021) trial. However, venetoclax-based non-intensive regimens have not been analyzed with this method. Methods: We performed a retrospective, longitudinal analysis of data gathered from a single-center cohort. All newly diagnosed, >60 years old patients with upfront management with venetoclax-based non-intensive chemotherapy combined with LDAC or hypomethylating agents (HMA) at our institution were included. TOX time was defined as the period of time before remission and/or time with serious adverse events (SAE) as defined by Office for Human Research Protections (OHRP) guidance (2007). REL time was defined as time from relapse until death, last follow-up or the start of a second line treatment, TWiST was defined as the time in remission and without SAEs. Q-TWiST analysis was performed as previously described (Solem CT, 2020). Results: We included 17 patients, 58.8% were male, mean age was 74 (70-78) years. The diagnosis was de novo AML in 52.9%, and secondary AML in 46.9%. European LeukemiaNet (ELN) risk was favorable in 5.8%, intermediate in 11.7% and adverse in 41.1%, 35.2% was unknown, FLT3-ITD mutations were present in 23.5%. 25% of the population had basal ECOG performance status ≥3, HCT-CI score was ≥3 in 47%. Considering the patients with baseline geriatric assessment: 14.2% were frail, 42.8% pre-frail and 42.8% robust. Venetoclax was combined with azacitidine in 35.2% and LDAC in 64.7%, 11.7% received additional midostaurin. Venetoclax dose was 100 mg/day in combination with strong CYP3A4 inhibitors (mainly itraconazole) in all patients. By last cycle, venetoclax was adjusted to <28 days in 76.6% of patients. Azacitidine dose was adjusted in 60% of patients, and LDAC in 9%. 76% of patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) with the treatment, 23.5% had no response and 28% relapsed. With a mean follow up of 42.4 (25.7-59.1), mean OS was 43.1 (95% IC 26.6-59.6), progression free survival (PFS) 37 (95% IC 19.1-54.8), Q-TWiST 36.3 (95% IC 19.7-53), and TWiST 30.3 (95% IC 13.5-47.1) weeks. Other variables related to toxicity are shown in table 1. Comparison with previously reported Q-TWiST with LDAC and 7+3 as frontline therapy in the elderly is described in Figure 1. Conclusions: the Q-TWiST in our unselected population was better than the Q-TWiST described for LDAC arm in the glasdegib trial, this is striking considering the comparison between real world data in a low-income setting with clinical trial population. This suggests that venetoclax-based non intensive chemotherapy not only offers longer OS but also longer quality-adjusted time compared to previous standard to this vulnerable population. When compared to 7+3 regimens the Q-TWiST was slightly shorter in our cohort,probably associated with the inclusion criteria of the trial, including ability to tolerate 7+3 regimen and an age limit of 75 years, which different from our population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal