Gemtuzumab Ozogamicin for Patients with Newly Diagnosed CD33 Positive Acute Myeloid Leukemia: Results from a French Retrospective Observational Study

International audienceIntroduction: Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate targeting CD33 with a calicheamicin derivative payload. GO is approved in France in combination with daunorubicin and cytarabine for treatment-naïve patients aged ≥15 years with de novo CD33-positive acute myeloid leukemia (AML). Before the European Medicines Agency granted marketing authorization in 2018, GO was available in France with an authorization for temporary use (ATU) for specific patients since 2010, and between 2018 and 2019 as part of a “post-ATU” cohort until its reimbursement. This study aimed to describe the real-world use, effectiveness, and safety of GO in treatment-naïve patients with CD33-positive AML in France, as requested by the French Transparency Commission. Methods: This retrospective, multicenter, observational study included all patients in the French ATU and post-ATU cohorts treated between 01 December 2014 and 31 October 2022. Patient and disease characteristics, treatment (dose/combination), response outcomes, and adverse events (AEs) of interest were described. Prognostic factors for event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS) were identified using Cox proportional hazard models. Results: Overall, 113 patients were included (ATU cohort, N=62; post-ATU cohort, N=51). The median age when GO was initiated was 63.0 years (range, 19-91); 54.9% (n=62) of patients were male; 81.8% (n=72/88) had an ECOG performance score 0-1, and 65.3% (n=64/98) had favorable risk according to the ELN classification 2017 ( Table). During the first induction treatment, most patients (98.1%; n=105/107) received GO in association with other agents, most commonly cytarabine and daunorubicin (60.0%; n=63/105). Most patients (78.5%, n=84/107) received 3 doses of GO during first induction. In all cases, patients received GO in second (7.1%; n=8) or subsequent (2.7%; n=3) induction courses - always in association with cytarabine and with or without daunorubicin/other agents. GO was given during the first, second, and subsequent consolidation treatment in 46.9% (n=53), 32.7% (n=37), and 2.7% (n=3) of patients, respectively, usually with cytarabine with or without daunorubicin. After a median follow-up of 44.6 months (95% CI, 33.8-69.3), 78.6% (n=88/112) of patients responded post-induction - of these, 72.3% (n=81) achieved a complete response (CR) and 6.3% (n=7) achieved a CR without platelet recovery. Minimal residual disease was evaluable in 46 patients; 52.2% (n=24) achieved a CR without minimal residual disease. Median EFS was 13.1 months (95% CI, 9.9-17.5); EFS by ELN risk group is shown in the Table. Median RFS was 17.5 months (95% CI, 12.6-35.6) and median OS was 49.8 months (95% CI, 21.8-not estimable; Figure). After a median period of 13.0 months (range, 3.0-33.0) following GO treatment, 31.5% (n=35/111) of patients received a hematopoietic stem cell transplant. Older age predicted shorter OS (hazard ratio [HR] 1.1 [95% CI, 1.0-1.1]; p<0.001). Having an FLT3TKD mutation (HR 4.1 [95% CI, 1.4-12.4]; p=0.013) or adverse cytogenetic classification (HR 13.0 [95% CI, 2.3-73.8]; p=0.015) predicted shorter EFS. Having ECOG-PS ≥2 (HR 6.6 [95% CI, 1.8-24.5]; p=0.005) or adverse cytogenetic classification (HR 72.7 [95% CI, 7.6-699.1]; p=0.001) predicted shorter RFS. AEs of interest were reported for 38.9% (n=44) of patients; 13.3% (n=15) were serious and 26.6% (n=30) were treatment-related (TRAE). The most common AEs were thrombocytopenia (21.2%; n=24), pyrexia (4.4%; n=5), and hepatic cytolysis (3.5%; n=4). AEs of special interest included persistent thrombocytopenia (15.9%; n=18), severe hemorrhage (5.3%; n=6), and veno-occlusive disease/sinusoidal obstruction syndrome (0.9%; n=1). Overall, 46.9% (n=53) patients died, with relapse or progressive disease accounting for 41.5% of deaths (n=22/53). Two (1.8%) patients died from TRAEs (laryngeal edema/pulmonary alveolar hemorrhage and hepatic cytolysis). Conclusions: GO was predominantly administered according to its indication. Response rates were similar to those reported in the pivotal ALFA-0701 study. Median OS was longer in this study than in ALFA-0701 (49.8 vs 27.5 months), although median RFS and EFS were reduced. No new safety signals were reported. Overall, GO appears safe and effective in real-world practice when added to induction therapy for treating patients with de novo CD33-positive AML

Allogenic Stem Cell Transplantation Abrogates Negative Impact on Outcome of AML Patients with KMT2A Partial Tandem Duplication

Recently, a new subset of acute myeloid leukemia (AML) presenting a direct partial tandem duplication (PTD) of the KMT2A gene was described. The consequences of this alteration in terms of outcome and response to treatment remain unclear. We analyzed retrospectively a cohort of KMT2A-PTD-mutated patients with newly diagnosed AML. With a median follow-up of 3.6 years, the median overall survival was 12.1 months. KMT2A-PTD-mutated patients were highly enriched in mutations affecting epigenetic actors and the RTK/RAS signaling pathway. Integrating KMT2A-PTD in ELN classification abrogates its predictive value on survival suggesting that this mutation may overcome other genomic marker effects. In patients receiving intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) significantly improved the outcome compared to non-transplanted patients. In the multivariate analysis, only HSCT at any time in complete remission (HR = 2.35; p = 0.034) and FLT3-ITD status (HR = 0.29; p = 0.014) were independent variables associated with overall survival, whereas age was not. In conclusion, our results emphasize that KMT2A-PTD should be considered as a potential adverse prognostic factor. However, as KMT2A-PTD-mutated patients are usually considered an intermediate risk group, upfront HSCT should be considered in first CR due to the high relapse rate observed in this subset of patients

Human myeloid differentiation by BMP4 signaling through the VDR pathway in acute myeloid leukemia

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Azacitidine for patients with Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) and myelodysplastic syndrome: data from the French VEXAS registry

International audienceAzacitidine can be effective in myelodysplastic syndromes (MDS) associated with inflammatory/autoimmune diseases. Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) is a new monogenic autoinflammatory syndrome caused by somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutation, often associated with MDS, whose treatment is difficult and not yet codified. Based on a French nationwide registry of 116 patients with VEXAS, we report the efficacy and safety of azacitidine treatment in 11 patients with VEXAS with MDS. Clinical response of VEXAS to azacitidine was achieved in five patients (46%), during 6, 8+, 12, 21, 27+ months respectively, suggesting that azacitidine can be effective in selected patients with VEXAS and associated MDS

Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

International audienceMinimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached ≥ 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; p < 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse

Use of tamibarotene, a potent and selective RARα agonist, in combination with azacitidine in patients with relapsed and refractory AML with RARA gene overexpression

International audienceTamibarotene-based therapy is a novel targeted approach for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with retinoic acid receptor alpha (RARA) gene overexpression. Approximately, 50% of higher-risk myelodysplastic syndrome (MDS) patients and approximately 30% of AML patients are positive for RARA overexpression using a blood-based biomarker test that measures RARA expression in peripheral blasts. A phase 2 study investigating the activity of tamibarotene in patients with RARA overexpression was conducted in patients with AML and MDS (NCT02807558). In 28 patients with R/R AML and RARA overexpression treated with tamibarotene in combination with azacitidine, the median overall survival was 5.9 months. In 21 response-evaluable patients, the complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate was 19%, and median time to initial CR/CRi was 1.2 months. The favorable safety profile and preliminary clinical activity support the development of combination therapies with tamibarotene in myeloid malignancies with RARA overexpression

The Impact of DNMT3A Status on NPM1 MRD Predictive Value and Survival in Elderly AML Patients Treated Intensively

International audienceSimple Summary DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of acute myeloid leukemia (AML) patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. A 4log reduction of NPM1 MRD was associated with a better outcome. DNMT3A negative patients who achieved a 4log reduction had a superior outcome to those who did not. However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identify a subgroup of patients at high risk of relapse. Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a >= 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached >= 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; p < 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse

Clinical outcome of therapy‐related acute myeloid leukemia patients. Real‐life experience in a University Hospital and a Cancer Center in France

Abstract Background t‐AML occurs after a primary malignancy treatment and retains a poor prognosis. Aims To determine the impact of primary malignancies, therapeutic strategies, and prognostic factors on clinical outcomes of t‐AML. Results A total of 112 adult patients were included in this study. Fifty‐Five patients received intensive chemotherapy (IC), 33 non‐IC, and 24 best supportive care. At t‐AML diagnosis, 42% and 44% of patients presented an unfavorable karyotype and unfavorable 2010 ELN risk profile, respectively. Among treated patients (n = 88), 43 (49%) achieved complete remission: four out of 33 (12%) and 39 out of 55 (71%) in non‐IC and IC groups, respectively. With a median follow‐up of 5.5 months, the median overall survival (OS) and disease‐free survival (DFS) for the whole population were 9 months and 6.3 months, respectively, and for the 88 treated patients 13.5 months and 8.2 months, respectively. Univariate analysis on OS and DFS showed a significant impact of high white blood cells (WBC) and blast counts at diagnosis, unfavorable karyotype and ELN classification. Multivariate analysis showed a negative impact of WBC count at diagnosis and a positive impact of chemotherapy on OS and DFS in the whole population. It also showed a negative impact of previous auto‐HCT and high WBC count on OS and DFS and of IC on OS in treated patients which disappeared when we considered only confounding variables (age, previous cancers, marrow blasts, and 2010 ELN classification). In a pair‐matched analysis comparing IC treated t‐AML with de novo AML, there was no difference of OS and DFS between the two populations. Conclusion We showed, in this study that t‐AML patients with unfavorable features represented almost half of the population. Best outcomes obtained in patients receiving IC must be balanced by known confounding variables and should be improved by using new innovative agents and therapeutic strategies