Advances in management of primary myelofibrosis and polycythaemia vera: Implications in clinical practice.

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.

First-line second generation tyrosine kinase inhibitors in patients with newly diagnosed accelerated phase chronic myeloid leukemia.

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.

Dasatinib plus Peg-Interferon alpha 2b combination in newly diagnosed chronic phase chronic myeloid leukaemia: Results of a multicenter phase 2 study (DASA-PegIFN study).

Superior 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.

Reduced peripheral blood dendritic cell and monocyte subsets in MDS patients with systemic inflammatory or dysimmune diseases.

BACKGROUND: Systemic inflammatory and autoimmune diseases (SIADs) occur in 10-20% of patients with myelodysplastic syndrome (MDS). Recently identified VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, associated with somatic mutations in UBA1 (Ubiquitin-like modifier-activating enzyme 1), encompasses a range of severe inflammatory conditions along with hematological abnormalities, including MDS. The pathophysiological mechanisms underlying the association between MDS and SIADs remain largely unknown, especially the roles of different myeloid immune cell subsets. The aim of this study was to quantitatively evaluate peripheral blood myeloid immune cells (dendritic cells (DC) and monocytes) by flow cytometry in MDS patients with associated SIAD (n = 14, most often including relapsing polychondritis or neutrophilic dermatoses) and to compare their distribution in MDS patients without SIAD (n = 23) and healthy controls (n = 7). Most MDS and MDS/SIAD patients had low-risk MDS. Eight of 14 (57%) MDS/SIAD patients carried UBA1 somatic mutations, defining VEXAS syndrome.Compared with MDS patients, most DC and monocyte subsets were significantly decreased in MDS/SIAD patients, especially in MDS patients with VEXAS syndrome. Our study provides the first overview of the peripheral blood immune myeloid cell distribution in MDS patients with associated SIADs and raises several hypotheses: possible redistribution to inflammation sites, increased apoptosis, or impaired development in the bone marrow.

Innovative approach to lymphadenectomy in breast sarcoma.

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 lymphadenectomy 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.

A randomised phase II study of azacitidine (AZA) alone or with Lenalidomide (LEN), Valproic acid (VPA) or Idarubicin (IDA) in higher-Risk MDS or low blast AML: GFM's "pick a winner" trial, with the impact of somatic mutations.

In order to improve the outcome observed with azacitidine (AZA) in higher-risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA-PLUS was a phase II trial that, in a "pick a winner" approach, randomly assigned patients with higher-risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six cycles, 69 (21.4%) CR + PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7 months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six cycles were higher in the AZA-LEN And AZA-IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy-related MDS and, in the case of TP53, PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our "pick a winner" randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA.

A New Modality for Breast Cancer Diagnosis During the COVID-19 Pandemic: A Case Report.

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.

Protective role of melatonin in breast cancer: what we can learn from women with blindness.

PURPOSE: This review proposes an overall vision of the protective and therapeutic role of melatonin in breast cancer: from the specific cases of blind women and their reduction of breast cancer incidence to all clinical uses of the sleep hormone in breast cancer. METHODS: We reviewed studies focused on (1) the correlation between blindness and breast cancer, (2) the correlation between melatonin and breast cancer occurrence in the general population, (3) melatonin therapeutic use in breast cancer, and (4) we discussed the properties of melatonin that could explain an anticancer effect. RESULTS: (1) Seven studies of breast cancer risk in blind women related significant incidence decreases, up to 57%, among totally blind women. The limited number of studies and the absence of adjustment for confounding factors in most studies limit conclusions. None of these studies established melatonin profiles to determine whether blind women with a decreased breast cancer incidence produced higher levels of melatonin. (2) In the general population, 5 meta-analyses and 12 prospective-cohort studies focused on melatonin levels at recruitment and breast cancer occurrence. All reported the absence of correlation in premenopausal women, whereas in postmenopausal women, most studies showed significantly decreased risk for women with highest melatonin levels. (3) The therapeutic interest of melatonin associated with chemotherapy, radiotherapy, and hormonotherapy is poorly documented in breast cancer to conclude on a positive effect. (4) Melatonin effects on mammary carcinogenesis were only reported in in vitro and animal studies that demonstrated antiestrogenic, antioxidant, oncostatic, and immunomodulatory properties. CONCLUSION: The preventive role of high endogenous melatonin on breast cancer as well as its beneficial therapeutic use remains to be proven.

New Data on the Epidemiology of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

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.

Breast Cancer Management During the COVID-19 Pandemic: The Senologic International Society Survey.

OBJECTIVE: In early 2020, the spread of coronavirus disease-2019 (COVID-19) led the World Health Organization to declare this disease a pandemic. Initial epidemiological data showed that patients with cancer were at high risk of developing severe forms of COVID-19. National scientific societies published recommendations modifying the patients' breast cancer (BC) management to preserve, in theory, quality oncologic care, avoiding the increased risk of contamination. The Senology International Society (SIS) decided to take an inventory of the actions taken worldwide. This study investigates COVID-19-related changes concerning BC management and analyzes the will to maintain them after the pandemic, evaluating their oncological safety consequences. MATERIALS AND METHODS: SIS network members participated in an online survey using a questionnaire (Microsoft® Forms) from June 15th to July 31st, 2020. RESULTS: Forty-five responses from 24 countries showed that screening programs had been suspended (68%); magnetic resonance imagines were postponed (73%); telemedicine was preferred when possible (71%). Surgeries were postponed: reconstructive (77%), for benign diseases (84%), and in patients with significant comorbidities (66%). Chemotherapy and radiotherapy protocols had been adapted in 28% of patients in both. Exception for telemedicine (34%), these changes in practice should not be continued. CONCLUSION: The SIS survey showed significant changes in BC's diagnosis and treatment during the first wave of the COVID-19 pandemic, but most of these changes should not be maintained. Indeed, women have fewer severe forms of COVID-19 and are less likely to die than men. The risk of dying from COVID-19 is more related to the presence of comorbidities and age than to BC. Stopping screening and delaying treatment leads to more advanced stages of BC. Only women aged over 65 with BC under treatment and comorbidities require adaptation of their cancer management.

Clinical Pharmacokinetics and Pharmacodynamics of Dasatinib.

Dasatinib is an oral, once-daily tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Dasatinib is rapidly absorbed, with the time for maximal serum concentration varying between 0.25 and 1.5 h. Oral absorption is not affected by food. The absolute bioavailability of dasatinib in humans is unknown due to the lack of an intravenous formulation preventing calculation of the reference exposure. Dasatinib is eliminated through cytochrome P450 (CYP) 3A4-mediated metabolism, with a terminal half-life of 3-4 h. Based on total radioactivity, only 20% of the oral dose (100 mg) is recovered unchanged in faeces (19%, including potential non-absorption) and urine (1%) after 168 h. Dasatinib pharmacokinetics are not influenced by age (children, and adults up to 86 years of age), race and renal insufficiency. Dasatinib absorption is decreased by pH-modifying agents (antacids, H2-receptor blockers, proton pump inhibitors), and dasatinib is also subject to drug interactions with CYP3A4 inducers or inhibitors.

Tuberculosis and atypical mycobacterial infections in ruxolitinib-treated patients with primary or secondary myelofibrosis or polycythemia vera.

Ruxolitinib is a JAK-1/JAK-2 inhibitor indicated for the treatment of polycythemia vera and primary or secondary myelofibrosis. Only one patient (0.2%) was diagnosed with tuberculosis among the 485 patients receiving ruxolitinib in the four pivotal trials. Fourteen cases of tuberculosis have since been reported. We observed two (3%) mycobacterial infections (one due to Mycobacterium tuberculosis and one due to Mycobacterium avium complex) in our cohort of 65 patients receiving ruxolitinib. This observation suggests that the rate of mycobacterial infection might be higher than that observed in the pivotal trials and that atypical mycobacterial infections can also occur.

Dyserythropoiesis evaluated by the RED score and hepcidin:ferritin ratio predicts response to erythropoietin in lower-risk myelodysplastic syndromes.

Erythropoiesis-stimulating agents are generally the first line of treatment of anemia in patients with lower-risk myelodysplastic syndrome. We prospectively investigated the predictive value of somatic mutations, and biomarkers of ineffective erythropoiesis including the flow cytometry RED score, serum growth-differentiation factor-15, and hepcidin levels. Inclusion criteria were no prior treatment with erythropoiesis-stimulating agents, low- or intermediate-1-risk myelodysplastic syndrome according to the International Prognostic Scoring System, and a hemoglobin level <10 g/dL. Patients could be red blood cell transfusion-dependent or not and were given epoetin zeta 40 000 IU/week. Serum erythropoietin level, iron parameters, hepcidin, flow cytometry Ogata and RED scores, and growth-differentiation factor-15 levels were determined at baseline, and molecular analysis by next-generation sequencing was also conducted. Erythroid response (defined according to the International Working Group 2006 criteria) was assessed at week 12. Seventy patients, with a median age of 78 years, were included in the study. There were 22 patients with refractory cytopenia with multilineage dysplasia, 19 with refractory cytopenia with unilineage dysplasia, 14 with refractory anemia with ring sideroblasts, four with refractory anemia with excess blasts-1, six with chronic myelomonocytic leukemia, two with del5q-and three with unclassifiable myelodysplastic syndrome. According to the revised International Prognostic Scoring System, 13 had very low risk, 47 had low risk, nine intermediate risk and one had high-risk disease. Twenty patients were transfusion dependent. Forty-eight percent had an erythroid response and the median duration of the response was 26 months. At baseline, non-responders had significantly higher RED scores and lower hepcidin:ferritin ratios. In multivariate analysis, only a RED score >4 (P=0.05) and a hepcidin:ferritin ratio <9 (P=0.02) were statistically significantly associated with worse erythroid response. The median response duration was shorter in patients with growth-differentiation factor-15 >2000 pg/mL and a hepcidin:ferritin ratio <9 (P=0.0008 and P=0.01, respectively). In multivariate analysis, both variables were associated with shorter response duration. Erythroid response to epoetin zeta was similar to that obtained with other erythropoiesis-stimulating agents and was correlated with higher baseline hepcidin:ferritin ratio and lower RED score. ClinicalTrials.gov registration: NCT 03598582.

Ponatinib evaluation and safety in real-life chronic myelogenous leukemia patients failing more than two tyrosine kinase inhibitors: the PEARL observational study.

Ponatinib represents a remarkable progress in the treatment of heavily pretreated chronic myelogenous leukemia (CML) and de novo Philadelphia chromosome-positive ALL patients despite significant toxicity in clinical trials. To date, "real-life" data remain few and the use of ponatinib in this setting and its consequences remain mostly unknown. We report, within a national observational study, the use of ponatinib in unselected CML patients who had previously failed ≥2 lines of tyrosine kinase inhibitor (TKI) therapy (or one line if an Abelson (ABL)T315I mutation was identified), in real-life conditions (2013-2014) in a compassionate program. Our analysis has been focused on 48 chronic phase CML patients recorded. With a median follow-up of 26.5 months since ponatinib initiation, the overall survival (OS) rates (80.5% at 3 years) and cumulative incidence of major molecular response (81.8% at 18 months) were similar to those of the phase II study, with no influence of BCR-ABL mutations nor the reason of ponatinib prescription. A specific subanalysis of the preexisting cardiovascular risk factors and events occurring on ponatinib is described. These events occurred after a median time on ponatinib of 5.8 months (excluding hypertension) and were observed in 29/48 patients (47%), even in those already on anti-aggregants/coagulants. The majority were not severe and resolved, but two cases were fatal. Other hematological or nonhematological nonvascular adverse events were similar to those previously described in trials. This observational study reports similar rates of survival, molecular responses, and a slight increase in the cardiovascular toxicity of ponatinib in real-life conditions, prompting improved control of cardiovascular risk factors and selection of patients.

Prospective evaluation of the effect of deferasirox on hematologic response in transfusion-dependent patients with low-risk MDS and iron overload.

OBJECTIVES: To assess the reduction of transfusions rate in transfusion-dependent patients with low-risk myelodysplastic syndrome (MDS) with iron overload treated with deferasirox. METHODS: Prospective observational study. Primary endpoint was reduction in transfusion requirements (RTR) at 3 months, (assessed on 8-week period). Secondary endpoints were hematologic improvement according to International Working Group (IWG) 2006 criteria at 3, 6, and 12 months. RESULTS: Fifty-seven patients were evaluable. After 3 months of chelation, no effect was seen on transfusion requirement (5.9 packed red blood cells (PRBC) vs 5.8 before chelation). According to the Kaplan-Meier analysis, the probability of RTR at 3, 6, and 12 months was assessed as 3.5%, 9.1%, and 18.7%, respectively. Median duration of RTR was 182 days. However, during the 12-month follow-up after deferasirox initiation, 17 patients (31.5%) achieved minor erythroid response [HI-E] according to IWG criteria, 10 of whom having achieved Hb improvement at month 12. CONCLUSION: After 3 months of treatment, deferasirox had no impact on transfusion requirement in regularly transfused patients with low-risk MDS. However, deferasirox could induce 31% of erythroid response during the 12-month follow-up period thus suggesting that iron chelation therapy with deferasirox may induce an effect on hematopoiesis in a subset of patients with MDS and iron overload.

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: Recommendations for clinical practice from the French Chronic Myeloid Leukemia Study Group.

BACKGROUND: The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice. METHODS: Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucémies Myéloïdes Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice. RESULTS: Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction. CONCLUSIONS: This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018;124:2956-63. © 2018 American Cancer Society.

Azacitidine improves outcome in higher-risk MDS patients with chromosome 7 abnormalities: a retrospective comparison of GESMD and GFM registries.

Treatment with azacitidine (AZA) has been suggested to be of benefit for higher-risk myelodysplastic syndrome (HR-MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR-MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time-varying variable in multivariable analysis. A Cox Regression model with time-interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non-CK) and International Prognostic Scoring System risk (high versus intermediate-2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P < 0·001 at 1 year, 0·7 P = 0·019 at 2 years; 0·73 P = 0·029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non-CK patients, P < 0·05 for all). AZA also significantly improved progression-free survival (P < 0·01). This study confirms a time-dependent benefit of AZA on outcome in patients with HR-MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK.

Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation.

During the last decade, the use of tyrosine kinase inhibitor (TKI) therapy has modified the natural history of chronic myeloid leukemia (CML) allowing an increase of the overall and disease-free survival, especially in patients in whom molecular residual disease becomes undetectable. However, it has been demonstrated that BCR-ABL1- expressing leukemic stem cells (LSCs) persist in patients in deep molecular response. It has also been shown that the discontinuation of Imatinib leads to a molecular relapse in the majority of cases. To determine a possible relationship between these two phenomena, we have evaluated by clonogenic and long-term culture initiating cell (LTC-IC) assays, the presence of BCR-ABL1-expressing LSCs in marrow samples from 21 patients in deep molecular response for three years after TKI therapy (mean duration seven years). LSCs were detected in 4/21 patients. Discontinuation of TKI therapy in 13/21 patients led to a rapid molecular relapse in five patients (4 without detectable LSCs and one with detectable LSCs). No relapse occurred in the eight patients still on TKI therapy, whether LSCs were detectable or not. Thus, this study demonstrates for the first time the in vivo efficiency of TKIs, both in the progenitor and the LSC compartments. It also confirms the persistence of leukemic stem cells in patients in deep molecular response, certainly at the origin of relapses. Finally, it emphasizes the difficulty of detecting residual LSCs due to their rarity and their low BCR-ABL1 mRNA expression.