Afin d’assurer la sécurité des patient(e)s atteints de leucémie myéloïde chronique (LMC) et de leurs enfants, le Fi-LMC (France intergroupe de la LMC) émet des propositions concernant les aspects de sexualité, contraception, fertilité, procréation, et allaitement. Le groupe de travail souligne : (1) la nécessaire collaboration hémato/andro/gynéco/pharmacologues ; (2) la prise en compte du risque thrombotique lié aux formes hyperleucocytaires ou thrombocytaires ainsi qu’à la grossesse elle-même ; (3) l’intérêt de discuter une auto-conservation de sperme ou d’ovocytes selon le risque individuel d’infertilité ; (4) la gestion personnalisée des grossesses. Les inhibiteurs de tyrosine kinase (ITKs) administrés durant la phase d’organogenèse sont tératogènes, exposant à un risque de fausse couche, un retard de croissance intra-utérin, des malformations fœtales. En cas de diagnostic de LMC pendant la grossesse, ou de grossesse non programmée, celle-ci peut se poursuivre sans qu’il soit systématiquement nécessaire de recourir à son interruption volontaire ou médicale. L’arrêt des ITK durant tout le premier trimestre est conseillé au profit d’une surveillance de BCR::ABL1 ou d’un traitement par interféron-α pégylé selon l’âge gestationnel et la situation hématologique. Dans l’objectif d’une grossesse programmée, de préférence en réponse moléculaire majeure ou profonde, plusieurs modalités de suspension des ITK sont proposées, basées sur leurs paramètres pharmacocinétiques et le profil de la patiente. À partir du deuxième trimestre, la reprise d’imatinib ou de nilotinib est possible. Le dasatinib doit être évité tout au long de la grossesse. Les données concernant bosutinib, ponatinib et asciminib restent insuffisantes. L’allaitement, s’il est souhaité, nécessite l’arrêt anticipé des ITK avant l’accouchement.

BACKGROUND:Second generation tyrosine kinase inhibitors (TKIs) have improved response rates in patients with chronic phase chronic myeloid leukaemia (CP-CML). Phase 2 trials demonstrated increased deep molecular response rates when combining second generation TKIs with pegylated interferon alfa (Peg-IFN). This trial aimed to evaluate the efficacy and the safety of combining nilotinib with Peg-IFN alfa-2a in patients with newly diagnosed CP-CML. METHODS:In PETALs, this open-label, randomised, multicentre phase 3 trial, we enrolled patients with newly diagnosed CP-CML from 27 French academic institutions via a centrally-generated electronic system in a 1:1 ratio to two groups: 300 mg oral nilotinib alone twice a day (the nilotinib only group) or 300 mg nilotinib twice a day combined with subcutaneous Peg-IFN (30 μg per week for the first month of treatment and 45 μg per week thereafter) for a maximum of 2 years. The randomly allocated patients were stratified by their Sokal index and European Treatment and Outcome Study long-term survival index. Eligible patients had major BCR::ABL1 transcripts, an Eastern Cooperative Oncology Group performance score of two or lower, who had never received TKIs, and were aged between 18 and 65 years. The primary endpoint was the cumulative rate of molecular response 4·5 (MR4·5; defined as BCR::ABL1 international scale [IS] of 0·0032% and lower), analysed in the intention-to-treat population (n=200). This trial is registered at ClinicalTrials.gov, NCT02201459, and is completed. FINDINGS:205 patients were enrolled between Aug 6, 2014, and Sept 29, 2016, after which five patients were declared ineligible and excluded, resulting in 200 patients being randomly allocated (99 to the nilotinib group and 101 to the combination group). The median age at diagnosis was 45 years (IQR 36-55); 130 patients (65%) were male and 70 (35%) were female. Median follow-up in this cohort was 67 months (IQR 32·6-70·6). The primary objective was met, with higher rates of MR4·5 in the combination group (24% [95% CI 16·0-34·1] vs 15% [8·6-24·2], p=0·048) at month 12. There were equivalent grade 3-4 haematological side effects in the both groups (14 vs 14) with a predominance for grade 3-4 thrombocytopenia without haemorrhages (six in the combination group vs five in the nilotinib group). Psychiatric grade 3-4 events occurred in six (6%) patients in the combination group (including three unsuccessful suicide attempts) compared with five (5%) in the nilotinib group (including one unsuccessful suicide attempt). Six vascular events also occurred in six patients in the combination group and seven vascular events in five patients in the nilotinib group (all grades 3-4). INTERPRETATION:In this setting, Peg-IFN combined with nilotinib induced higher initial rates of MR4·5 compared to TKI monotherapy, despite additional side effects. The onset of psychiatric events might promote immediate cease of Peg-IFN and psychiatrist advice Whether this early molecular response translates into sustained treatment-free survival should be studied in a randomised trial sufficiently powered for this outcome. FUNDING:Novartis Pharma.

In order to ensure safe outcomes for male and female patients with chronic myeloid leukemia (CML) and their children, the Fi-LMC group (France intergroupe de la LMC) discusses strategies regarding sexuality, contraception, fertility, procreation and breastfeeding. The working group underlines (1) the need for close collaboration between hematologists, andrologists, gynecologists/obstetricians and pharmacologists; (2) the importance of considering the thrombotic risk at diagnosis in case of marked hyperleucocytosis or thrombocytosis, as well as during pregnancy; (3) the need to discuss sperm banking or oocyte cryopreservation according to the individual risk of infertility; (4) personalized pregnancy management. Tyrosine kinase inhibitors (TKIs) administered during organogenesis are teratogenic, exposing to a risk of fetal loss, intrauterine growth restriction and congenital malformations. In cases of CML diagnosed during pregnancy, or unplanned pregnancy, continuation of pregnancy is generally possible without requiring systematic voluntary or medical termination. TKIs should be withheld during the entire first trimester, in favor of BCR::ABL1 monitoring or pegylated interferon-α depending on gestational age and hematologic presentation. For planned pregnancies, ideally in major or deep molecular response, several TKI withdrawal strategies are proposed, depending on their pharmacokinetics and on the patient's profile. From the second trimester onwards, imatinib or nilotinib can be reintroduced if needed. Dasatinib must be avoided throughout pregnancy. Data on bosutinib, ponatinib and asciminib remain insufficient. For patients wishing to breastfeed, TKIs must be discontinued sufficiently prior to delivery.

Information about Diamond-Blackfan anemia syndrome (DBAS), a ribosomopathy associated with anemia, congenital anomalies and cancer predisposition is limited in adults. Using the French DBAS registry, 235 adult patients with DBAS were analyzed for hematological outcomes. At last follow-up, anemia, neutropenia, thrombocytopenia, and pancytopenia affected respectively 78%, 31%, 15%, and 11% of the patients. There was no severe aplastic anemia outside of clonal evolution. Among patients without DBAS-specific treatment (e.g., steroids or red blood cell transfusions), the incidence of anemia, neutropenia, and thrombocytopenia was 52%, 35%, and 10%, highlighting that treatment independence does not mean hematologic remission. Four patients developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), all associated with poor-risk features and dismal outcomes. Observed to expected ratios were 155 for MDS and 55.4 for AML, confirming a major risk-excess despite stringent criteria for MDS diagnosis. With a median follow-up of 32.2 years (IQR 26-44), overall survival (OS) was 98.0% (95% CI, 95.8-100), 90.6% (95% CI, 84.2-97.5), and 70.7% (95% CI, 57.3-87.2) at 30, 40, and 50 years respectively. Solid and hematologic cancers were the main cause of death. This study demonstrates, in a large cohort of adults with DBAS, that cytopenias beyond anemia are frequent and persistent. Myeloid neoplasms occur with a high incidence and dismal outcomes. These findings highlight the need for risk stratification, tailored surveillance, and optimized therapeutic strategies in this vulnerable population.

Therapeutic management of metastatic cancer patients who are hospitalized at the time of initial diagnosis because of impaired performance status and/or severe symptoms is challenging for clinicians. This study aims to describe their outcome. In this prospective multicentric study, we included all adult, inpatients with newly diagnosed metastatic solid tumors between November 2021 and May 2022. Patients were followed for 3 months.. Our primary objective was to describe overall survival (OS). Secondary objectives included assessing SANT effectiveness in specific subgroups, identifying baseline factors associated with SANT initiation, and assessing usual prognostic tools and factors associated with response. 107 patients were included. Seventy-four (69

Recently, the presence of a variety of AGA to the BCR-ABL1 oncogene in CP-CML has been described to impair the prognosis of this disease and response to TKIs. We have taken the opportunity of the Trial of Imatinib After Ponatinib Induction (TIPI) to explore such consequences by NGS targeting the most frequently mutated lympho-myeloid genes in AL, in newly diagnosed CP-CML patients (pts) undergoing this sequential therapy. . TIPI is an open-label phase II national academic trial (Clinical Trial: NCT04070443) for newly diagnosed adult CP-CML pts ≤65 years, harbouring major BCR::ABL1 transcripts. The primary endpoint is the rate of pts reaching TFR criteria at M36. Pts were treated with ponatinib 30 mg QD for 6 months, followed by a de-escalation with imatinib 400 mg QD until TFR criteria (MR4.5 ≥2 years) are reached, before M60. Molecular assessments were centralised and BCR::ABL1/ABL1 transcripts expressed in % on the international scale. BCR::ABL1 TKD mutations were screened by NGS. AGA were assessed by NGS (30-genes panel). Only VAF>5% were retained as pathological. The MMEJ signature was inferred from the BCR::ABL1 breakpoint sequences determined by an asymmetric capture sequencing strategy, as described by H. Guerineau et al (AJH 2025; 100: 507–510). One hundred and sixty nine pts were enrolled between November 2019 and October 2022, median age was 48 (18-65) years, 113 pts were males (67%) and 15 (9%) pts harboured additional chromosomal abnormalities (ACA). Eighty-four (51.5%) pts had b2a2 and 99 (61%) b3a2 transcripts and could eventually harbour both. ELTS were low for 67 (40%), intermediate for 73 (44%) and high for 27 (16%) pts, data unavailable for 2. The median follow-up was 18 (2.8-46.1) months. The CI of MR4 and MR4.5 were respectively 33 (26-40)% and 10 (5-14)% at M12; 40 (33-48)% and 13 (8-18)% at M18. One possible toxic death and 2 progressions (1 MBC, 1 LBC) occurred, resulting into death after allo-SCT. Only 3ABL1 mutations (2%) were observed, [1 on ponatinib, E255K at M6 (MBC pt), and 2 M244V on imatinib]. Full clinical results have already been presented (Nicolini FE et al. ASH 2024). At the time of writing, 148 patients were sequenced on diagnosis samples and mutated clones are followed-up and presented, on ponatinib and further on imatinib. We compared pts with AGA (n=30, 20%) with pts with no AGA (n=118). Thirty patients (20%) were harbouring AGA consisting in ASXL1 (n=18, 60%), KDM6A (n=3, 10%), DNMT3A (n=2, 7%) IKZF1, RUNX1, SETD1B, BCORL1, BCOR, TET2 and WT1 (n=1 each, 3.3%) and 24/133 (18%, 15 MD) patients showed a MMEJ signature. There was no difference between the 2 groups in age and sex. ACA were present in 4/30 patients with AGA (13%) and in 5/117 (1 MD, 4%) patients without AGA. Sokal score was low in 45%, intermediate in 36% and high in 19% of pts with AGA versus low in 17%, intermediate in 33% and high in 50% of pts without AGA (p<0.001). ELTS score was low in 40.5%, intermediate in 47.5% and high in 12.5% of patients with AGA versus low in 30%, intermediate in 37% and high in 33% of pts without AGA (p=0.02). While the 18-month cumulative incidence (CI) of MMR and MR4 were not different between the 2 groups, the CI of MR4.5 was significantly higher in the AGA group 24% (8.2-40.2) vs without AGA 10.25% (4.73-15.78) with HR=2.62 (95% CI: 1.03-6.64), p=0.043 in univariate analysis. Moreover, the presence of MMEJ had a strong negative impact on the 18-month CI of MR4.5: 0% with MMEJ vs 16.5% (9.5-23.5) without MMEJ p<0.001. The MMEJ+ versus MMEJ- groups show no difference except the ELTS intermediate + high scores were higher in the MMEJ+ group (p=0.016). Neither the presence of AGA nor the presence of MMEJ had an impact on 18-month EFS (p=0.38 and p=0.166 respectively). Interestingly, one of the 2 BC that occurred harboured AGA at diagnosis (WT1, VAF=6%) but no MMEJ signature. Multivariate analysis adjusted on MR4.5 at M18 identified the presence of AGA as beneficial [HR=3.46 (1.29-9.26), p=0.014].The kinetics of AGA on sequential treatment by ponatinib followed by imatinib will be presented. Twenty percent of newly diagnosed CP-CML harbour AGA at diagnosis that significantly impact on molecular response at 18 months on sequential therapy by ponatinib followed by imatinib. Additionally, the role of MMEJ seems to have a strong negative impact on obtaining deep molecular response.

Introduction: There is still an unmet medical need for patients with low riskmyelodysplastic syndrome (MDS) who are refractory or relapsing to erythropoietin stimulating agents and transfusion dependent. Transfusion burden leads to iron overload needing iron chelation therapy. In vitro data from our team demonstrate that low dose of deferasirox (DFX) (3µM) induced MDS erythroid progenitors proliferation by decreasing oxidative stress (Meunier al, Oncotarget 2017). Several case reports from patients under iron chelation therapy have already shown an improvement of hemoglobin level. Thus, we initiated a multicenter study named LODEFI, prospectively assessing the potential benefit of low dose deferasirox on transfusion burden for low risk MDS patients. Methods: This is a single arm, multi-center, open-label, Phase II trial for patients with very low, low and intermediate myelodysplastic syndrome according to IPSS-R and WHO 2016 classification, refractory or relapsing to erythropoietin stimulating agents, with low transfusion burden and ferritin level under 1000 µg/l.Deferasirox 3.5mg/kg was given orally every day for 12 months. Baseline patient characteristics and biology including iron metabolism data were collected. Primary endpoint was the efficiency of low dose DFX on transfusion dependence at one year from the beginning of DFX, defined by the need of 2 and more red blood cells units per 8 weeks on 3 time periods of 8 weeks (24 weeks), from the 6th to the 12th month of the beginning of DFX. Some of the secondary endpoints were to assess the impact of low dose DFX on transfusion dependance (TD) defined as a transfusion burden of more than 4 red blood cells units every 8 weeks on an evaluation period of 24 weeks and to evaluate the clinical and biological tolerability of low dose of DFX in this population of patients. Results: Between February 2018 and April 2023,thirty-eight patients were enrolled with a median age of 73.5 years (interquartile range (IR): 69.0-78.0 years). Of these, 57.9% were male and the median Charlson index was 4 (IR: 3-5). MDS subtype were: MDS-SLD (8), MDS-RS (14), MDS-MLD (8), CMML-1 (1), MDS EB-1 (3) and MDS-U (4). The IPSS-R categories for the patients were very low (16), low (19) and intermediate (1), NA (2). The median hemoglobin level at inclusion was 86 g/L (IR: 81- 97) and the median ferritin level was 547µg/L (IR: 399; 849). The baseline biological parameters in MDS-RS versus the other MDS subtypes were: a lower median hemoglobin level (84g/L vs 88g/L), a higher median transferrin saturation (80% vs 50%, p=0.005) with a tendency for higher median non-transferrin-bound iron (NTBI) level (1.49 vs 1.00µmol/L), and a lower median hepcidin level (3.5ng/ml vs 16.4ng/ml, p=0.007). The majority of patients (86.8%) were considered non-TD according to IWG 2018 and 13.2% were low transfusion burden. All patients had received ESA prior to deferasirox. All patients received DFX at inclusion at 3.5mg/kg. Residual dosages of DFX were done at month 1 (M1) to adapt the dosage at M3 to reach around 3µM. The dosage of DFX was decreased in 26.3% of patients (mainly in MDS-RS patients) and increased in 15.8% of them. The primary objective was met: we observed a transfusion independence (TI) at 12 months in 47.4% (CI-95%: 31.0%; 64.2%) of the patients treated by DFX. If we used a more stringent definition of transfusion dependence described in secondary endpoints, we observed a TI at 12 months in 68.4% (CI 95%: 51.3%; 82.5%) of the patients treated by DFX. TI rate according to primary endpoint was numerically lower in MDS-RS than in the other types of MDS (28.6% vs 58.3%). Low dose DFX was also well tolerated (mainly grade 1 to 3 digestive, auditive renal adverse reactions), with only one diabetic patient having overdose of DFX and renal and hepatic impairment leading to DFX discontinuation. Conclusion: Low dose DFX induces 47.4% of transfusion independency at M12 in low risk MDS anemic patients refractory or relapsing to ESA, with a favorable tolerance profile. It could be a potential treatment option for anemia in selected MDS patients who are refractory or relapsing to ESA and with low transfusion burden.

Introduction: Prevention ofdisease transformation and long-term achievement of sustained deep molecular response (DMR) followed by successful treatment-free remission (TFR) are the current main goals of treatment of CP-CML. This trial addressed the safety and efficacy of a 6-month debulking strategy using ponatinib as front-line therapy in newly diagnosed CP-CML, followed by maintenance with imatinib. This was intended to induce a high proportion of TFR, with minimal toxicity. This is an update after an 18-month follow-up. Methods: TIPI is an open-label phase II national academic trial (Clinical Trial: NCT04070443) that enrolled newly diagnosed adult CP-CML patients (pts) ≤65 years, harbouring major BCR::ABL1 transcripts with no significant underlying cardio-vascular disease, uncontrolled hypertension or diabetes with end-organ damage. Pts were stratified according to ELTS scores. Primary endpoint is the rate at which pts reached TFR criteria at M36 (Rea et al. Cancer, 2018). Two of the secondary endpoints are the kinetics of molecular response and its safety during this 2-TKI strategy. Pts were treated with ponatinib 30 mg QD for 6 months, followed by imatinib 400 mg QD until TFR criteria (MR4.5 ≥2 years) were reached, before M60. Molecular assessments were centralised and BCR::ABL1 transcripts were expressed in % on the international scale (IS). BCR::ABL1 mutation screens were performed by NGS. Results were analysed on an intention-to-treat basis. Results:One hundred and sixty nine pts were enrolled between November 2019 and October 2022. Median age was 48 (18-65) years, 113 pts were males (67%). Fifteen (9%) pts harboured additional chromosomal abnormalities (ACA). Eighty-four (51.5%) pts had b2a2 and 99 (61%) b3a2 transcripts and could eventually harbour both. ELTS were low for 67 (40%) pts, intermediate for 73 (44%) and high for 27 (16%), data unavailable for 2. European Society of Cardiology (ESC) score was <2% in 158/167 (93%) evaluable pts, 3-9% in 8 (5%) pts and >10% in 1 (2%) pt. The median follow-up at database lock was 18 (2.8-46.1) months. Induction data (M1→M6) have already been presented (FE. Nicolini et al, ASH 2023). After M6, median number of days on imatinib is 365 (19-365) and median dose of imatinib delivered between M6 → M18 is 400 (295-480) mg daily. Whereas a total of 39 grade 3-5 AEs had been recorded at M18, only a minority (n=13, 33%) were observed on imatinib: 2 hematologic (grade 4 neutropenia at M6) and 11 non-hematologic SAEs (2 urinary tract perturbations and 1 of each of the following: grade 4 transaminitis, seizure, diplopia, deep vein thrombosis, breast cancer, baso-cellular carcinoma, Covid-19 infection, appendicitis, gonarthrosis). Interestingly, no cardio-vascular event occurred on imatinib. The event-free survival [(EFS), event = death from any cause, progression, permanent discontinuation of study treatment related to AEs, study withdraw] is 92 (87.5-95.95)% at M6, 88.7 (84-94)% at M9, 87.5 (83-93)% at M12, 86 (82-92)% at M18. Regarding efficacy, 158 pts/163 (97%) were in EMR on ponatinib. At M6 following the end of ponatinib induction the cumulative incidence (CI) of MMR was 44 (37-52)% , and then on imatinib, 59 (52-67)% at M9, 65 (58-72.5)% at M12 and 68 (60.5-75)% at M18 . The CI of MR4 and MR4.5 were respectively 23 (16-29)% and 7 (3-10)% at M6, 32 (25-39)% and 8 (4-13)% at M9, 33 (26-40)% and 10 (5-14)% at M12; 40 (33-48)% and 13 (8-18)% at M18 These data indicate that consolidation by imatinib did not significantly impair the molecular levels previously obtained on ponatinib. A few (n=7, 8%) patients lost their MMR previously obtained at M6 on ponatinib, and this occurred more often in younger patients [28 (23-45.5) years vs 48 (39-56), p=0.048]. A total of 3 pts died, one from sudden death at M2.5, and 2 in blast crisis at M3 and M8, from allogeneic SCT-related complications. BCR::ABL1 mutations were identified in 3 patients one with E255K at M6 (MBC pt) and 2 with a M244V at M18. Conclusions:We observed a significant decrease in SAEs while on imatinib as compared to during the ponatinib induction phase. Ponatinib induction followed by imatinib consolidation induces high rates of MMR and DMR at M18, higher than that with TKI2 as front-line therapy as reported in the literature in CP-CML pts. Whether or not this translates into substantial TFR rates is yet to be determined.

Purpose Therapeutic management of metastatic cancer patients who are hospitalized at the time of initial diagnosis because of impaired performance status and/or severe symptoms is challenging for clinicians. This study describes their outcome and the effect of systemic anti-neoplastic treatment (SANT) initiation on survival. Methods In this prospective multicentric study, we included all adult, inpatients with newly diagnosed metastatic solid tumors. Our primary objective was to describe overall survival (OS). Secondary objectives included assessing SANT effectiveness, identifying factors influencing initiation of SANT, and assessing usual prognostic tools and factors associated with response. Results 107 patients were included over a six-month period. Seventy-four (69%) initiated a SANT. Among them, 39 patients were alive at 3 months. Median overall survival was 1.7 months for the entire cohort. Thirty-seven patients (55%) died in the unit where they were first admitted. Patients with chemo-sensitive tumors or targeted therapy for specific molecular alterations showed better outcomes. Factors associated with the initiation of a SANT were young age (OR = 0,94 [0,90; 0,98]), low Charlson Comorbidity Index (OR = 0,56 [0,42; 0,73]), and patient’s or caregiver’s request for treatment (OR = 0,07 [0,02; 0,17] and 0,17 [0,06; 0,42], respectively). Conclusion Metastatic cancer patients hospitalized at the time of diagnosis share a similar poor survival. With the notable exception of chemosensitive tumors and specific molecular alterations, initiation of SANT seems to have a limited impact on their outcomes. Best supportive care can be reasonably considered for these patients. The benefit of SANT in this altered population should be assessed in larger prospective studies.

Little is known about metastatic cancer patients who are hospitalized at diagnosis because of impaired performance status and/or severe symptoms. This study aims to explore their prognosis and the effect of systemic anti-neoplastic treatment (SANT) initiation on their outcomes. A prospective multicentric study of adult inpatients with a newly diagnosed metastatic solid tumor was conducted in seven cancer-facilities in France. During a three-month follow-up, socio-demographic characteristics, response rate and duration of response for patients receiving SANT, length of hospital stay and survival were collected. Correlation with clinical prognostic and predictive factors was analyzed. 107 patients were included from November 2021 to April 2022. Seventy-four (69%) underwent SANT. Median overall survival was 1.7 months for the entire cohort. Forty (37%) were alive at 3 months, including 39 patients that started SANT. Factors associated with the initiation of a SANT were young age (OR=0,94 [0,90; 0,98]), low Charlson Comorbidity Index (OR=0,56 [0,42; 0,73]), SANT initiated at patient’s or caregiver’s request (OR=0,07 [0,02; 0,17] and 0,17 [0,06; 0,42], respectively). Patients with biomarker-based targeted therapy had better outcomes at 3 months, while survival of patients treated with exclusive immunotherapy was poor. PALLIA-10 score superior to 5 was a significant predictive factor for mortality (HR=3,24; p<0,001). Metastatic cancer patients hospitalized at the time of diagnosis share a similar poor survival. The initiation of SANT does not always impact their outcomes. Larger prospective studies with longer follow-up are needed to better assess the effect of SANT in this population.

Breast cancer is extremely rare in children and consequently no consensus has been reached on the optimal treatment modalities. We have reported the medical history of secretory breast carcinoma (SBC) in a 6-year-old girl. An areolar-sparing mastectomy was performed without axillary surgery, and without adjuvant therapy given her limited disease and the histological type. We have reviewed the literature and summarized relevant findings concerning the clinical and histological data, treatment approaches, and outcomes for 33 cases of SBC (15 children and 18 adolescents). International data suggests that local excision without axillary surgery may be a suitable therapeutic approach for children with SBC.

Introduction: The prevention ofdisease transformation which typically occurs during the first years of treatment, is one of the critical goals of the treatment of CP-CML with TKI. In addition, treatment free remission (TFR) represents now another major challenge. In vitro data show that ponatinib is one of the most powerful inhibitors of wild-type as well as mutated BCR::ABL1 TK and this has been translated in heavily pre-treated CML patients (pts) intolerant or resistant to other compounds. In this trial we assessed the safety and efficacy of a 6-months debulking strategy using ponatinib as front-line therapy in newly diagnosed CP-CML, followed by a maintenance with imatinib, in order to bring a high proportion of pts in TFR. Methods: This open-label phase II national academic trial (Clinical Trial: NCT04070443) enrolled newly diagnosed adult CP-CML pts ≤65 years, with a major BCR::ABL1 transcript and no significant underlying cardio-vascular disease, uncontrolled hypertension or diabetes with target organ damage, QTc prolongation and with adequate organ functions. They were stratified according to the ELTS score. The primary endpoint is the impact of ponatinib induction on the rate of pts reaching TFR criteria as defined by our group (Rea et al. Cancer, 2018) at M36. Secondary endpoints were the safety and clinical activity of this strategy, ponatinib pharmacokinetics (PK), QoL under both inhibitors and compliance. Pts were treated with ponatinib 30 mg QD for 6-months, followed by imatinib 400 mg QD until TFR criteria (i. e. MR4.5 ≥2 years) would been reached before M60. All molecular assessments were centralised and BCR::ABL1 transcripts were expressed in % on the international scale (IS). This analysis relies on the intention-to-treat principle. Results: One hundred and seventy-eight pts were screened, 170 enrolled and 169 treated between November 2019 and October 2022. Median age was 48 (18-65) years, 113 pts were males (67%). One pt had a cryptic Ph, and 15 (9%) pts harboured additional chromosomal abnormalities (ACA). Eighty-four (51.5%) pts had b2a2 and 99 (61%) b3a2 transcripts knowing that they could harbour both. ELTS were low for 67 (40%) pts, intermediate for 73 (44%) and high for 27 (16%). For 2 patients it could not be calculated (1 splenectomy, 1 no spleen assessment). European Society of Cardiology (ESC) score was <2% in 158/167 (93%) evaluable pts, 3-9% in 8 (5%) pts and >10% in 1 (2%) pt. One hundred and one (60%) pts never smoked, 46 (27%) were past smokers. The median follow-up at database lock was 18 (3-33) months. Only induction data are presented here. The median number of days on ponatinib is 172 (1-193) and the median dose of ponatinib delivered is 30 (16.5-32) mg daily. Overall, 135 grade 3-5 AEs occurred after a median of 51 (0-186) days: 123 (91%) grade 3, 11 (8%) grade 4 and 1 fatal AE; 49 (36%) were hematologic, and 86 (64%) non-hematologic, and 109 (81%) were considered as related to study treatment. Seven pts (5%) discontinued permanently ponatinib, and 56 (41.5%) received the full planned dose. Six (4.5%) Grade 3-5 cardiac events (1 fatal cardiac arrest) and 17 (12.5%) vascular events (15 newly hypertensive pts, 1 pulmonary embolism? 1 carotid stenosis) occurred. Their cumulative incidence is shown in Figure 1A. Digestive & clinical hepato-biliary events occurred in 10 (7.5%), infections in 7 (5%), lipase elevation in 15 (11%) and liver enzymes elevation in 20 (15%) pts. Eye, skin and neurologic events occurred in less than 2% of pts. Regarding efficacy, 147 evaluable pts/158 (93%) were in CHR at M1, 115 in CCyR (70.5%) at M3 and 158/163 (97%) in EMR. The median halving time (calculated with ABL1 as a reference gene) was 13.5 (11.5-17.5) days. The cumulative incidence of molecular response is shown in Figure 1B. Fourty-seven pts over 157 assessable (30%) were in deep molecular response at M6. One (0.6%) pt transformed into myeloid blast crisis, alive in CR before transplant. PK data and their relationship with safety and efficacy will be presented. Univariate analysis identified the halving time as the only factor impacting on MR4.5 at M6. Conclusions: Ponatinib displays high anti-leukemic activity as front-line therapy in selected newly diagnosed CP-CML pts with high early molecular response rates with non-negligible severe -in particular cardio-vascular- toxicity at 30 mg QD. Whether or not this will be translated into substantial TFR rates will be determined at later time points.

Introduction. Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a median age of approximately 60 years. Our study emphasizes the fact that CML can present at younger ages. These patients have significantly different life challenges compared with older patients. The 2020 update of the ELN recommendations mentioned that“ TFR may be the main goal for any patient, irrespective of age, but it is clear that the younger the patient the stronger the case for achieving TFR”. We report here the main characteristics and TFR data in CML young adults. Methods. The French CML group (FI-LMC) initiated an observational study (CCTIRS no. 14.745) to describe the characteristics of CML in young adult patients in terms of characteristics at diagnosis, treatment choices, tolerance, adherence, therapeutic response, evolution and survival. Patients ranging from 18 to < 30 years with newly diagnosed CML in chronic phase (CP) or accelerated phase (AP) treated with a tyrosine kinase inhibitor (TKI) in first line were eligible for enrolment. Results. The observatory included 253 unselected young adults from 22 centers with newly diagnosed CML in CP (n=246) or in AP (n=7) among which 51.6% were treated within a first line trial. At the time of CML diagnosis, the median patient age was 24 years (range, 18-29 years); 165 patients were males (63%). Median (range) values were: WBC 154.3 G/L (6.5; 841); platelets 374 G/L (51; 1799), hemoglobin 11.3 g/dL (4.1; 18.3), blast cells 1 % (0; 20), spleen below costal margin 4 cm (0; 30). In CP patients, Sokal score was low in 132 (53.6%) patients, intermediate in 46 (18.7%), high in 37 (15.1%) and unknown in 31 (12.6%) and ELTS score was low in 142 (57.7%) patients, intermediate in 48 (19.5%), high in 22 (9%) and unknown in 34 (13.8%). Initial TKI was imatinib alone (52.4%) or in combination with IFN (2.4%) or Ara-C (0.8%), nilotinib alone (24.6%) or in combination with IFN (4%), dasatinib alone (8.2%) or in combination with IFN (0.4%), bosutinib (1.2%), ponatinib (4.8%) or asciminib (1.2%). Median follow-up is 106.2 months (range: 0.03; 279.2). Ninety-nine (39.3%) patients remained under first-line TKI at latest follow-up and 21 pts (8.3%) underwent bone marrow transplantation (BMT) for resistance or transformation. Median overall survival at 9 years is 96.9% [95% CI: 94.5- 99.4]. Event free survival without death, transformation, or BMT at 9 years is 93.1% [95% CI: 89.7- 96.7]. Six patients died, 1 from sarcoma, 5 from CML including 1 before any therapy (brain hemorrhage). We investigated the TFR strategy. In 169 patients treated for at least 5 years, 56 (33.1%) attempted TKI discontinuation. TKI free survival at 24 months is 57.9% [95% CI: 45.8- 73.2] (Figure 1). Complete analysis comparing characteristics and outcome between the 2 groups of patients (TFR vs no TFR), will be available for ASH presentation. Conclusion. Despite aggressive features including prominent splenomegaly, high WBC counts and high blast cell percentage, TFR seems achievable in young adults with CML.

Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare BCR-ABL1-negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic complications and progression to fibrosis or leukaemia or fibrosis for PV. Both diseases are characterised by biological and clinical heterogeneity, leading to great variability in their management in routine clinical practice. In this review, we present an updated overview of the diagnosis, prognosis and treatment of PMF and PV, and we discuss how our multidisciplinary expert group based across France translates this evidence-based knowledge into routine clinical practice.

Accelerated phase (AP) CML at onset and have poorer prognosis than CP-CML. We hypothesize that off-license use of second generation TKI (TKI2) as front-line therapy might counterbalance this poor prognosis, with limited toxicity. In "real-life" conditions, newly diagnosed patients meeting the ELN cytological criteria for AP-CML or harboring ACA and treated with first-line TKI2 were included in this retrospective multicenter observational study. We enrolled 69 patients [69.5 % male, median age 49.5 years, median follow-up 43.5 months], segregated into hematologic AP [HEM-AP (n = 32)] and cytogenetically defined AP [ACA-AP (n = 37)]. Hematologic parameters were worse in HEM-AP [spleen size (p = 0.014), PB basophils (p < .001), PB blasts (p < .001), PB blasts+promyelocytes (p < .001), low hemoglobin levels (p < .001)]. Dasatinib was initiated in 56 % patients in HEM-AP and in 27 % in ACA-AP, nilotinib in 44 % and 73 % respectively. Response and survival do not differ, regardless of the TKI2: 81 % vs 84.3 % patients achieved CHR, 88 % vs 84 % CCyR, 73 % vs 75 % MMR respectively. The estimated 5-year PFS 91.5 % (95%CI: 84.51-99.06 %) and 5-year OS 96.84 % (95%CI: 92.61-100 %). Only BM blasts (p < 0.001) and BM blasts+promyelocytes (p < 0.001) at diagnosis negatively influenced OS. TKI2 as front-line therapy in newly diagnosed AP-CML induce excellent responses and survival, and counterbalance the negative impact of advanced disease phase.

OBJECTIVE:This study aimed to illustrate the epidemiological situation of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) by focusing on the changes published after 2019 and particularly the new approaches of cosmetic and reconstructive breast surgery.MATERIALS AND METHODS:Article search was performed from January 2019 to date using the PubMed database. Fourteen articles were included in the qualitative evaluation of international data. Moreover, the latest reports regarding the total number of BIA-ALCL cases and number of deaths were identified.RESULTS:Estimates of the risk and incidence have increased significantly recently, affecting 1 in every 2,969 women with breast implants and 1 in 355 patients with textured implants after breast reconstruction. The average exposure time to diagnosis was 8 (range: 0-34) years. Approximately 80% of BIA-ALCL cases were diagnosed at IA-IIA stages, for which the treatment was breast implant removal, full capsulectomy, and excision of all suspected lymph nodes. Globally, at least 949 cases were reported to date.CONCLUSION:At present, BIA-ALCL is an emerging pathology of interest. Data collection initiated since 2016 through different case registration databases is essential to ensure surveillance and to continue to increase the number of studies on this recently discovered pathology.

Introduction Thrombosis is the main cause of morbidity in myeloproliferative neoplasms (MPN) and can be the mode of revelation of these malignant diseases. Most of them are characterized by specific driver mutations such as JAK2 V617F, CALR or MPL. An idiopathic or atypical thrombotic event justifies looking for MPN by searching these MPN-related mutations, even in the absence of myeloproliferative features on the complete blood count (CBC). This is especially crucial in case of splanchnic and cerebral thromboses, but not only. In this context the diagnosis of MPN and the choice of treatment are made difficult by the absence of increased blood counts. Objectives - To constitute an observational cohort of patients (pts) presenting an arterial or venous thrombotic event leading to a suspicion of MPN without signs of myeloproliferation in CBC. - To study the characteristics of pts at diagnosis, the rate of recurrence of thrombosis and the rate of hematological progression. Patients and method Inclusion criteria were as follows: i)-diagnosis of an arterial or deep venous thrombotic event, ii)-CBC not suggestive of polycythemia vera (PV), essential thrombocythemia (ET) or myelofibrosis (MF) (CBC below WHO 2016 thresholds) but iii)-detection of a molecular abnormality (JAK2, CALR or MPL driver mutations) and/or an abnormality on bone marrow trephine in favor of MPN and/or spontaneous progenitor growth. Data were collected retrospectively and prospectively. The study is registered on ClinicalTrial.gov (NCT04539678). Results Between 05/2019 and 06/2022, the participation of 31 centers in France and Switzerland allowed the collection of data from 216 pts. The analysis is presented for 208 pts after exclusion of incomplete non-evaluable cases (n=5) or those not meeting inclusion criteria (n=3). The M/F sex ratio was 1.3 with a median age of 55 years (22-91) at the date of molecular testing. Inaugural thrombosis was venous (80%) or arterial (20%) and involved either splanchnic (50%), cerebral (24%), other locations (23%) or multiple territories (3%). Median CBC values were hemoglobin 14 g/dL, hematocrit 43%, platelets 298x109/L and leukocytes 7,1 x109/L. Pts had either a driver mutation of JAK2 V617F (n=201), CALR (n=2) or MPL (n=2), or none of these but spontaneous progenitor growth (n=3). According to WHO criteria, the diagnoses retained were MPN in 91 (44%) cases (including 26 PV, 4 MF and 61 unclassifiable MPN), while 38 pts (18%) lacked MPN criteria and 79 (38%) were not assessable (no trephine). A clinical follow-up of at least 3 months was available in 197 pts, with a median of 61 months (range 3 months - 36 years). Recurrent thrombosis occurred for 42 pts (21%, respectively 24% of initially arterial and 19% of initially venous). Recurrence was splanchnic for 13 pts (31%). The median delay of recurrence was 37 months (12 days - 18 years) after the thrombotic event that led to a suspicion of MPN. Recurrence occurred more often in pts with initially non-splanchnic thrombosis (30% vs. 13% p=0.004). Thrombosis recurrences were not significantly different between pts classified as MPN and those without MPN criteria (18% vs. 30% p=0.1). Hematological progression was observed for 27 pts with a median delay of 31 months (1 - 105) since thrombosis. According to WHO MPN criteria, they were 9 PV, 14 TE and 4 MF. Pts with thrombotic recurrence more frequently presented hematological progression or died (31 month progression-free survival [PFS] 85% vs 94% p=0.008). PFS was significantly reduced in cases of initially non-splanchnic thrombosis (86% vs 97% at 31 months p<0.0001). An explanation could be that pts with splanchnic thrombosis were more frequently treated with cytoreductive agents (CRA) (71% vs 41% p=0.03). Analysis of the effect of antithrombotic therapy is ongoing. Conclusion Thrombosis cases with a non-proliferative CBC but with MPN driver mutations leading to MPN suspicion constitute a heterogeneous group of pts, with many cases of non-splanchnic involvement. The latter pts show more frequent thrombotic recurrences and hematological progression than pts with splanchnic involvement. The role of cytoreduction and antithrombotic therapies needs to be explored in this context.

Lymphatic dissemination is thought to be a rare event in breast sarcomas. The decision to perform axillary clearance is challenging. In our prospective cohort, we aimed to evaluate the frequency and factors determining lymph node (LN) involvement in breast sarcomas, with the aim of proposing a decision tree/algorithm for the realization of LN clearance in breast sarcomas. Patients and methods > Fourty-five women were surgically treated for breast sarcomas from 1982 to 2020. Angiosarcomas and other sarcomas were compared in terms of LN involvement, recurrence, and mortality.Results > Twenty-three patients underwent axillary lymphadenectomy. Initial LN involvement was diagnosed in one case of D2-40 positive, primary angiosarcoma for which preoperative imaging detected a suspicious LN confirmed by preoperative histology. Among the 22 patients who had no initial axillary lymphadenectomy, two patients with D2-40 positive angiosarcoma had recurrent cancer in LN (internal mammary group in 1 and homolateral axilla in 1). The average follow-up in the overall population was 6.2 years (+/- 8.3). The cohort's overall recurrence rate was 33% (15/45) and the time of recurrence after initial surgery was on average 2.4 years (+/- 3.1). For the three patients with LN metastases, time to recurrence after surgery was 3.7 years (+/- 4.5). There was no significant difference in the overall recurrence rate depending on whether or not lymphadenec-tomy was initially performed (respectively 26% vs 41% OR = 1.11, P = 0.29). Discussion/Conclusion > Systematic axillary clearance leads to overtreatment in breast sarcomas. A decision tree, including radiological examination of the axilla, histological type of sarcoma, and D2-40 positivity, could be a decision aid in the choice of axillary clearance.

SummarySuperior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated‐interferon‐alpha (Peg‐IFN) in patients with newly diagnosed chronic phase‐chronic myeloid leukaemia (CP‐CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg‐IFN‐α2b (Dasa‐PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg‐IFNα‐2b add‐on therapy at month 3 for a maximum 21‐months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5) by 12 months. The results are reported for the 5‐year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3–4) and expected. Seventy‐nine per cent and 61% of patients continued the Peg‐IFN until months 12 and 24, respectively. Overall, at these time points, MR4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR4.5 or MR4, respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment‐free‐remission) with dasatinib and Peg‐IFNα‐2b combination as initial therapy.

Organized screening for breast cancer (BC) was suspended in most countries of the world during the coronavirus disease-2019 (COVID-19) pandemic. Com-puted tomography (CT) scans of the chest, frequently performed in patients with severe forms of COVID-19, may detect asymptomatic breast abnormalities. A 72-year-old patient, with a severe form of COVID-19 underwent a diagnostic CT scan. This led to the unexpected discovery, at an early stage, of a 12 mm, high grade, Human epidermal growth factor receptor 2 positive BC, with a high proliferation index. After responding to chemotherapy, she was managed with conser-vative breast surgery with sentinel lymph node biopsy. Delayed management of BC can be responsible for poor outcomes. Patients with severe forms of COVID-19 are also at risk for developing BC due to common risk factors. Thirty percent of incidental breast lesions discovered on CT scans are undiagnosed BC. Careful study of the mammary glands on CT scan of patients with COVID-19 may allow early diagnosis of a malignant tumor in a high-risk population for BC and deprived of routine screening mammography.