Impact of Early Access Reform on Oncology Innovation in France: Approvals, Patients, and Costs.

BACKGROUND: An ambitious reform of the early access (EA) process was set up in July 2021 in France, aiming to simplify procedures and accelerate access to innovative drugs. OBJECTIVE: This study analyzes the characteristics of oncology drug approvals through the EA process and its impact on real-life data for oncology patients. METHODS: The number and characteristics of EA demands concerning oncology drugs submitted to the National Health Authority (HAS, Haute Autorité de Santé) were reviewed until 31 December 2022. A longitudinal retrospective study on patients treated with an EA oncology drug between 1 January 2019 and 31 December 2022 was also performed using the French nationwide claims database (Systeme National des Données de Santé [SNDS]) to assess the impact of the reform on the number of indications and patients, and the costs. RESULTS: Among 110 published decisions, the HAS granted 88 (80%) EA indications within 70 days of assessment on average, including 46 (52%) in oncology (67% in solid tumors and 33% in hematological malignancies). Approved indications were mostly supported by randomized phase III trials (67%), whereas refused EA relied more on non-randomized (57%) trials. Overall survival was the primary endpoint of 28% of EA approvals versus none of denied EAs. In the SNDS data, the annual number of patients with cancer treated with an EA drug increased from 3137 patients in 2019 to 18,341 in 2022 (+ 484%), whereas the number of indications rose from 12 to 62, mainly in oncohematology (n = 17), lung (n = 12), digestive (n = 9) and breast cancer (n = 9). Reimbursement costs for EA treatments surged from €42 to €526 million (+ 1159%). CONCLUSION: The French EA reform contributed to enabling rapid access to innovations in a wide range of indications for oncology patients. However, the findings highlight ongoing challenges in financial sustainability, warranting continued evaluation and adjustments.

[Assessment of professional practices on the use of computerized medicine cabinets by registered nurses]. / Évaluation des pratiques professionnelles sur l'utilisation des armoires informatisées de stockage des médicaments par les infirmiers diplômés d'état.

Ensuring the safety of patient medication management is a public health priority. In hospitals, the medication circuit involves risks, especially in terms of storage. As part of an institutional project, the deployment of computerized medicine cabinets in our hospital's care units was initiated in 2015. By 2022, almost all care departments were equipped. Each drug picking is carried out by the registered nurse according to the patient's name, in accordance with the administration plan. In addition, local recommendations are to collect medication for a maximum of 24hours. In this context, our objective was to assess nursing professional practices in order to identify the steps requiring action plans. To meet this objective, we i) studied the compliance of computerized drug samplings with prescriptions on a given day throughout the establishment, ii) assessed picking practices with an observational audit, and iii) proposed questionnaires, including practical cases and satisfaction questions. Over 300 prescriptions were analyzed, including 2,511 drugs requiring at least one collect on the day of the assessment. The compliance rate for picking in relation to the drugs prescribed was 44.7%. According to the audit observation, the picking compliance rate was 74.5%. Non-compliances were mainly linked to the selection of the wrong patient at the computerized medicine cabinet and/or to a picking for longer than the recommended duration. Finally, the rate of correct answers to the proposed cases was 61.9%, and nurses were generally satisfied or very satisfied with the equipment.

[Reform of early access program in France: Impact on workload in a pharmacy and risk identification]. / Réforme de l'accès dérogatoire : impact sur la gestion dans une PUI et identification des risques.

The reform of derogatory access authorisations (DAs) on 1st July 2021 has distorted the routine of the hospital pharmacists dealing with innovative medicines that are waiting for marketing authorization or approval. There are two distinct categories of DAs: Compassionate Access Authorisations (CAAs) are granted by the French National Agency for the Safety of Medicines (ANSM) while Early Access Authorisations (EAPs) are granted at the request of pharmaceutical companies by the French National Authority for Health (HAS). All AAPs and a majority of the AACs are supported by a Protocol for Therapeutic Use and Data Collection (PTU-DC). The aim of this study is to assess the impact of the reform on pharmacy process one year following its implementation, and to identify the risks related to the new circuits. The working group, composed of three pharmacists carried out an initial assessment of the effects first measured the impact of the reform on medicine processes in DAs. They performed a comparison of the changes in their management methods: 3 months prior to the reform (M0), and 3 (M3) and 12 months (M12) post-reform. Risks analysis was conducted using the Failure Modes, Effects and Criticality Analysis (FMEA) method. The analysis was limited to the process steps specific related to DAs drugs were analyzed. The critical severity of the risk situations identified was rated. A critical hierarchy matrix was used to establish priority actions. The priority actions to be taken were determined using the critical hierarchy matrix. Over the span of one year, the number of DAs in our establishment showed a 31.7% increase, from 41 at M0 to 54 at M12. At M0, the proportion of drugs needed inclusion via a drug-specific digital platform, specific to each drug, stood at 27% (11/41) of drugs at M0 while at M12, it rose to 52% (28/54). The percentage of PTU-DCs therefore increased by a factor of 1.7, rising from 29% (12/41) at M0 to 47% (21/45) at M3 and 60% (32/54) at M12. For orders, which are always nominative, approval depends on both the presence of the PTU-DC tracking sheet being present in 12% of PAAs, and the inclusion number in 26% of PAAs. The risk analysis shows 49 failure modes leading to risk situations. Among the failure modes, 36 have a consequence of acceptable or tolerable criticality under control, whilst 13 are deemed of unacceptable criticality. A suitable control method exists has been identifies for 5 of them. Finally, the ranking evaluation of criticalities has highlighted 4 situations which require immediate action as a priority: delivery times, obtaining completed tracking sheets and ordering procedures. The aim of the DAs reform is to simplify access to innovative medicines. However, the reform has significant and damaging repercussions on pharmaceutical activities. Corrective measures need to be taken in conjunction with all parties involved in the circuits including laboratories and service providers (CROs), authorities and healthcare professionals.

Residual chemotherapy drugs after flushing infusion lines.

INTRODUCTION: During administration of chemotherapies, disconnection presents risks for nurses. Thus, it is recommended to flush the infusion line with solvent to reduce this risk and ensure that the entire dose is administered. Objectives of this study were to evaluate flushing practices and to investigate the efficiency of flushing, according to the type of hospitalization, in hospitalization (HU) or day-care unit (DCU), for three drugs. METHODS: Twenty secondary infusion lines were collected in five HU and 20 in two DCU. Flushing volumes were estimated by weighing solvent bags. The amount of residual drug was measured for secondary lines by mass spectrometry coupled with high-performance liquid chromatography. RESULTS: Chemotherapies were administered by 26 nurses. All of infusion lines contained chemotherapy after flushing. Flushing volumes, residual concentrations and flushing efficiencies were significantly different between these two types of units. In contrast, flushing volumes administrated did not differ between chemotherapy drugs. CONCLUSIONS: Local recommendations are fully implemented in HU and partially in DCU. The use of small volumes in DCU is related to the patient length of stay, it may, also, be due to omitting the average tubing volume. All infusion lines still contained chemotherapy, including those with a flush volume much higher than recommended, showing that the risk of exposure persists. To achieve a rinse volume greater than 50 mL, it is necessary to use at least 100 mL. It is also important to insist on personal protective equipment and to consider closed safety system for administration.

[Antibody drug conjugates (ADC) and bispecific antibodies in oncology - report of the 2022 Saint Louis day]. / Anticorps monoclonaux conjugués et bispécifiques en cancérologie ­ compte rendu de la Journée de Saint Louis 2022.

Antibody Drug Conjugates (ADC) and bispecific antibodies are booming and were the subject of the scientific event proposed by the French Society of Oncological Pharmacy, October 13, 2022. An ADC is composed of the antibody targeting a receptor expressed on the tumor cell, the spacer making it possible to attach the cytotoxic to the antibody and to control its distribution in the body, and the cytotoxic. Therapeutic antibodies, monoclonal and conjugated, have particular pharmacokinetics. Unlike monoclonal antibodies for which the standard dose is most often fixed, this is expressed in mg/m2 (or mg/kg) and capped at 2m2 (or 100kg) for conjugates. The linked cytotoxics are powerful cytotoxics: mitotic spindle poisons (emtansine, monomethyl auristatin E or vedotin), topoisomerase I inhibitors (deruxtecan, SN 38) or antibiotics (ozogamicin). In senology, trastuzumab deruxtecan (anti-HER2) and sacituzumab govitecan (anti-Trop 2) are now modifying treatment standards for patients with metastatic breast cancer, respectively HER2 3X or HER2 low and triple negative. In metastatic bladder cancer, enfortumab vedotin (anti-nectin 4) is positioned as the 2nd line of treatment. Bispecific antibodies, on the other hand, are able to target two epitopes, an antigen specific to a tumor cell and one to an immune cell, allowing a bridge between the killer immune cells and the tumor cells. For lymphoma proliferation, many bispecific antibodies are in development. The most advanced are glofitamab, epcoritamab and mosunetuzumab, which target the CD20 of B lymphocytes and the CD3 of T lymphocytes. Bispecific antibodies are also emerging in the treatment of myeloma with teclistamab and elranatamab (anti-CD3 and anti-BCMA) or talquetamab (anti-GPRC5D and anti-CD3). Conjugated antibodies, and more recently bispecific antibodies, are potential game changers in cancer treatment and researchs are needed to improve their efficacy and safety.

Context of instauration and evolution under isavuconazole, a 2-year prospective real-life study.

To describe reasons for initiation and evolution under isavuconazole (ISZ), a 2-year prospective and observational study was performed. Anonymized data collected during the first 3 months of treatment were indications of treatment, efficacy, overall survival (OS), evolution of toxicity markers, and ISZ trough levels. Fifty-one (26 invasive aspergillosis, 16 prophylaxis, and 9 mucormycosis) patients started on isavuconazole. Isavuconazole was initiated upfront in 12/51 cases, especially to avoid toxicities from other antifungals. As second-line therapy (39/51 patients), isavuconazole was mostly initiated after toxicities of the previous treatments (66.7%; 26/39 cases). An improvement in toxicity markers was reported in most patients. However, five patients experienced adverse events. The mean ISZ trough levels measured from 179 samples collected in 37 patients was 3.33 ± 1.64 mg/l. The mean ISZ through levels was significantly lower (P = .003) in alloHSCT recipients (3.10 ± 1.45 mg/l) than in other patients (3.76 ± 1.88 mg/l) but still within the expected range of efficacy. After 12 weeks, the OS was 69.2% (n = 18/26) in the invasive aspergillosis intention-to-treat (ITT) group and 44.4% (n = 4/9) in the mucormycosis ITT group. After 2 years, the OS was respectively 46.2% (n = 12/26) and 33.3% (n = 3/9) in these two groups.

Isavuconazole is commonly prescribed as second-line therapy after the toxicity of a previous treatment. In most cases, an improvement is reported. The well tolerability of isavuconazole was associated with correct blood levels, even in alloHSCT recipients.

[Medication adherence in renal transplantation: Evaluation, predictive factors and impact on humoral alloreactivity]. / Adhésion médicamenteuse en greffe rénale : évaluation, facteurs prédictifs et impact sur l'allo-réactivité humorale.

OBJECTIVES: The aims of this study were to assess medication adherence to immunosuppressive treatment in kidney transplanted patients, to identify predictive factors of medication non-adherence and to analyse its impact on the development of Donor Specific Antibodies (DSA) de novo, biomarkers of rejection in transplant recipients. METHODS: A cross-sectional single-centre study was conducted to assess medication adherence to immunosuppressive treatment with the BAASIS (Basel Assessment of Adherence Scale for Immunosuppressives) self-report questionnaire. Univariate and multivariate analyses were performed to determine non-adherence predictive factors and its role in the development of DSA de novo. RESULTS: A total of 212 renal transplanted patients completed the BAASIS questionnaire: 36,3 % were non-adherent to their immunosuppressive treatment. Patient's age and taking azathioprine were independent predictors of non-adherence and "married or living together" family status was a protective factor in the multivariate analysis. Medication non-adherence was associated with DSA de novo development in the multivariate model and it multiplied their risk of development by 3. CONCLUSIONS: This study, which detected a large proportion of patients who did not adhere to immunosuppressive treatment, highlighted non-adherence predictors and showed the association between non-adherence and development of DSA de novo. In case of non-adherent behavior, it is crucial to set up a personalised support for patients with a multidisciplinary approach of therapeutic education, in which the clinical pharmacist has a role.

Positron emission tomography-imaging assessment for guiding strategy in patients with relapsed/refractory large B-cell lymphoma receiving CAR T cells.

The aim of this study was to evaluate the prognostic impact of the F-fluorodeoxyglucose positron emission tomography response at 1 month (M1) and 3 months (M3) after anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in a multicenter cohort of 160 patients with relapsed/refractory large B-cell lymphomas (R/R LBCL). In total, 119 (75%) patients reached M1 evaluation; 64 (53%, 64/119) had a complete response (CR); 91% were Deauville Score (DS) 1-3. Progressionfree survival (PFS) and overall survival (OS) were significantly worse in patients with DS-5 at M1, than in patients with DS 1-3 (PFS hazard ratio [HR]=6.37, 95% confidence interval [CI]: 3.5-11.5 vs. OS HR=3.79, 95% CI: 1.7-8.5) and DS-4 (PFS HR=11.99, 95% CI: 5.0-28.9 vs. OS HR=12.49, 95% CI: 2.8-55.8). The 1-year PFS rates were 78.9% (95% CI: 58.9-89.9) for DS-4 at M1, similar to 67.3% (95% CI: 51.8-78.8) for patients with DS 1-3 at M1, very different to 8.6% (95% CI: 1.8-22.4) for DS-5, respectively. Only eight of 30 (26%) patients with DS-4 progressed. Response at M3 evaluated in 90 (57%) patients was prognostic for PFS with lower discrimination (HR=3.28, 95% CI: 1.5-7.0; P=0.003) but did not predict OS (HR=0.61, 95% CI: 0.2-2.3; P=0.45). Patients with a high baseline total metabolic tumor volume (TMTV) >80 mL had worse PFS (HR=2.05, 95% CI: 1.2-3.5; P=0.009) and OS (HR=4.52, 95% CI: 2.5-8.1; P<0.001) than patients with low TMTV. Multivariable analyses identified baseline elevated lactate dehydrogenase, DS-5, CAR T cells at M1 for PFS and baseline elevated lactate dehydrogenase, TMTV >80 mL, and DS-5 at M1 for OS. In conclusion, baseline TMTV and response at M1 strongly predicts outcomes of patients with R/R LBCL undergoing CAR T-cell therapy.

The use of ICU resources in CAR-T cell recipients: a hospital-wide study.

BACKGROUND: CAR-T cell (chimeric antigen receptor T) therapy has emerged as an effective treatment of refractory hematological malignancies. Intensive care management is intrinsic to CAR-T cell therapy. We aim to describe and to assess outcomes in critically ill CAR-T cell recipients. STUDY DESIGN AND METHODS: Hospital-wide retrospective study. Consecutive CAR-T cell recipients requiring ICU admission from July 2017 and December 2020 were included. RESULTS: 71 patients (median age 60 years [37-68]) were admitted to the ICU 6 days [4-7] after CAR-T cell infusion. Underlying malignancies included diffuse large B cell lymphoma (n = 53, 75%), acute lymphoblastic leukemia (17 patients, 24%) and multiple myeloma (n = 1, 1.45%). Performance status (PS) was 1 [1-2]. Shock was the main reason for ICU admission (n = 40, 48%). Isolated cytokine release syndrome (CRS) was the most common complication (n = 33, 46%), while 21 patients (30%) had microbiologically documented bacterial infection (chiefly catheter-related infection). Immune effector cell-associated neurotoxicity syndrome was reported in 26 (37%) patients. At ICU admission, vasopressors were required in 18 patients (25%) and invasive mechanical ventilation in two. Overall, 49 (69%) and 40 patients (56%) received tocilizumab or steroids, respectively. Determinant of mortality were the reason for ICU admission (disease progression vs. sepsis or CRS (HR 4.02 [95%CI 1.10-14.65]), Performance status (HR 1.97/point [95%CI 1.14-3.41]) and SOFA score (HR 1.16/point [95%CI 1.01-1.33]). CONCLUSIONS: Meaningful survival could be achieved in up to half the CAR-T cell recipients. The severity of organ dysfunction is a major determinant of death, especially in patients with altered performance status or disease progression.

Negative Relationship between Post-Treatment Stromal Tumor-Infiltrating Lymphocyte (TIL) and Survival in Triple-Negative Breast Cancer Patients Treated with Dose-Dense Dose-Intense NeoAdjuvant Chemotherapy.

Background: Patients with triple-negative breast cancers (TNBC) have a poor prognosis unless a pathological complete response (pCR) is achieved after neoadjuvant chemotherapy (NAC). Few studies have analyzed changes in TIL levels following dose-dense dose-intense (dd-di) NAC. Patients and methods: From 2009 to 2018, 117 patients with TNBC received dd-di NAC at our institution. We aimed to identify factors associated with pre- and post-NAC TIL levels, and oncological outcomes relapse-free survival (RFS), and overall survival (OS). Results: Median pre-NAC and post-NAC TIL levels were 15% and 3%, respectively. Change in TIL levels with treatment was significantly correlated with metabolic response (SUV) and pCR. High post-NAC TIL levels were associated with a weak metabolic response after two cycles of NAC, with the presence of residual disease and nodal involvement at NAC completion. In multivariate analyses, high post-NAC TIL levels independently predicted poor RFS and poor OS (HR = 1.4 per 10% increment, 95%CI (1.1; 1.9) p = 0.014 and HR = 1.8 per 10% increment 95%CI (1.3−2.3), p < 0.0001, respectively). Conclusion: Our results suggest that TNBC patients with TIL enrichment after NAC are at higher risk of relapse. These patients are potential candidates for adjuvant treatment, such as immunotherapy, in clinical trials.

Effect of early granulocyte-colony-stimulating factor administration in the prevention of febrile neutropenia and impact on toxicity and efficacy of anti-CD19 CAR-T in patients with relapsed/refractory B-cell lymphoma.

Chimeric Antigen Receptor T cells (CAR-T) are an outbreaking treatment option for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common specific toxicities, while severe neutropenia and infections are often observed as well. From March 2020, early G-CSF prophylaxis at day (D) two post-infusion was systematically proposed. We then compared patients treated before that date who did not receive G-CSF or who received late (after D5) G-CSF as control group. Patients administered with early G-CSF had similar duration of grade 4 neutropenia but significantly decreased incidence of febrile neutropenia (58% versus 81%, p = 0.018). Similar rate of toxicities was observed, including overall and grade 3-4 CRS (p = 0.93 and p = 0.28, respectively), and overall and grade 3-4 ICANS (p = 0.62 and p = 0.88, respectively). We observed no difference in the quality of CAR T-cells expansion (p = 0.79, %Cmax), nor in response rate (best ORR, 57.6% vs 61.8%, p = 0.93), nor survival even in a group of patients adjusted by a propensity score. In conclusion, early G-CSF administration was safe and effective in reducing febrile neutropenia without impact on toxicities nor on anti-lymphoma activity of CAR-T.

Advanced therapy medicinal products: Regulatory framework, hospital and pharmaceutical circuits in Europe and France.

Advanced therapy medicinal products (ATMPs) represent a new class of biological medicines. The European regulation has classified ATMPs into three categories: gene therapy medicinal products, somatic cell therapy medicinal products, and Tissue-Engineered products. If one of these categories incorporates a medical device, the medicine is defined as a Combined ATMP. The specificity and complexity of these innovative drugs have required a complete reorganization of hospital and pharmaceutical circuits, from patient eligibility to drug administration. Indeed, increased interaction and collaboration between different healthcare professionals are essential in order to guarantee quality and safety of these innovative medicines.

ATMP Environmental Exposure Assessment in European Healthcare Settings: A Systematic Review of the Literature.

Since 2007, a new class of biologic products for human use called "advanced therapy medicinal products (ATMP)" have been legally integrated in the European Medical Agency. They consist of recombinant nucleic acid, engineered cells, cells, or tissues. In the United States, ATMP fall under the regulatory framework of biological products and the term "cell and gene therapy product" is used in the legislative and regulatory documents. Potential clinical applications are broad, particularly, in the field of cancer, inherited genetic disease, and regenerative medicine. Indeed, the benefit conferred by CD19 chimeric antigen receptor T cells led to the first engineered cell therapy products to be approved by the Food and Drug Administration (FDA) in 2017. Gene therapy products to treat orphan diseases are also extensively developed with many clinical trials ongoing in the world. Nevertheless, the use of these therapeutic products is complex and requires careful considerations in the terms of regulatory and hospital setting requirements, such as storage, handling, administration, and disposal which justify the implementation of a secured medication circuit. Through this systematic review of the literature, the authors wanted to compile data on the assessment of environmental exposure related to the use of ATMP in healthcare setting to secure their medication circuit. A literature search was conducted on PubMed and Web of Science, and 32 publications dealing with environmental exposure assessment and ATMP were selected. In addition, marketed ATMPs were identified and data regarding the environmental concerns were extracted from product information sections from European Public Assessment Reports (EPAR). The environmental contamination assessments were mainly addressed in the reviews rather than in original articles related to the use of ATMP. Most of the product information sections from EPAR suggested precautions rather than requirements when dealing with environmental consideration following ATMP handling. Nevertheless, these precautions usually remain elusive especially concerning waste disposal and the detection of biological material on the work surfaces, and mainly relate to the genetically modified organisms (GMO) over non-GMO cellular products. Pharmaceutical oversight and adherence to the good preparation practices and good clinical practices are essential to ensure the safe use in term of environmental concern of these new therapeutic products in healthcare setting.

[CAR-T cells gene therapy medicines: Regulatory status and pharmaceutical circuits in Europe and France]. / Les médicaments de thérapie génique CAR-T cells : statuts réglementaires et circuits pharmaceutiques en Europe et en France.

CAR-T cells belong to a new class of biological medicines, referred to as Advanced Therapy Medicinal Products (ATMPs). Despite the cellular component, according to the regulatory definition, CAR-T cells are gene therapy medicines, a sub-category of ATMPs, since their therapeutic effect is the result of their genetic modification. The specificity and the complexity of these innovative drugs have required a complete reorganization of the hospital and pharmaceutical circuits, from the cell collection to the drug administration to the patient. Indeed, increased interaction and collaboration between different healthcare professionals is essential in order to guarantee the quality and safety of these innovative medicines.

Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia.

Tisagenlecleucel therapy has shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, relapses occur in 30-50% of patients. Determinants for CD19pos versus CD19neg relapses are poorly characterized. We report on 51 patients with R/R BCP-ALL (median age 17 years) infused with tisagenlecleucel after lymphodepletion. Complete remission rate at D28 was 96%. Prior blinatumomab increased the risk of early failure at D28. The 18-month cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 51%, 44%, and 74%, respectively, at a median follow-up of 15.5 months. Factors associated with a high tumor burden (occurrence of cytokine release syndrome) and prior blinatumomab were associated with an increased CIR, and a shorter EFS and OS. Pre-lymphodepletion high disease burden (MRD ≥ 10-2, SHR 10.4, p = 0.03) and detectable MRD at D28 (SHR 7.2, p = 0.006) correlated with an increased risk of CD19neg relapse. Low disease burden (SHR 5.3, p = 0.03) and loss of B-cell aplasia (BCA) (SHR 21.7, p = 0.004) predicted an increased risk of CD19pos relapses. These data highlight the impact of prior therapy on patient outcome. Finally, detectable MRD at D28 and loss of BCA both define patients at high risk of relapse for whom additional interventions are needed.

Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM).

PURPOSE: TP53-mutated (TP53m) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions. PATIENTS AND METHODS: This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients. RESULTS: Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset (P < .01) and higher age (P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively. CONCLUSION: In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.