Lambert Busque

Hôpital Maisonneuve-Rosemont | HMR · Hématologie

Objective Childhood maltreatment is associated with shorter leukocyte telomere length (LTL). However, the influence of cardiac vagal control on this relation is unknown. We examined whether cardiac vagal control at rest and in response to stress moderates or cross-sectionally mediates the relationship between childhood maltreatment and LTL. Method...

Among 281 patients with essential thrombocythemia and calreticulin mutation, we found a variant allele frequency of >60% to be associated with significantly shortened myelofibrosis-free survival, mostly apparent with CALR type-1 and CALR type-indeterminate mutations.

Background. A mutation in calreticulin ( CALRm) is found in 30-35% of patients (pts) with Essential Thrombocythemia (ET). There are 2 main CALRm mutation types, Type 1/Type 1 like (T1) a 52bp deletion, and Type 2/Type 2 like (T2) a 5bp insertion. Other atypical mutations (T3) occur in a minority of pts. Recent study ( Guglielmelli P et al, BCJ 2023...

Background: Classic myeloproliferative neoplasms (MPN) polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), are characterized by concurrent risk of thrombotic and hemorrhagic complications. These risks are reported to be further compounded perioperatively ( Blood, 2008), though scarce contemporary data exist. Further, the...

Background: Oral decitabine/cedazuridine (ASTX727) is a fixed dose combination of decitabine (35 mg) and the cytidine deaminase inhibitor cedazuridine (100 mg) given once daily X 5 days on a 28-day cycle producing pharmacokinetic (PK) exposure equivalent to the standard intravenous (IV) decitabine regimen of 20 mg/m 2 daily X 5 days on a 28-day cyc...

Background: Myeloproliferative neoplasms (MPN) are associated with significant symptom burden, influencing patient quality of life and management. Thorough assessment of this burden is crucial; however, data from large populational registries are limited. Our objective was to characterize symptom burden in a large MPN cohort, determining: i) age-as...

Multiple studies have reported a significant treatment‐free remission (TFR) rate of 50%–60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re‐initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should b...

Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP‐CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD‐eligible patients, we conduct...

Background: Asciminib is a novel drug specifically targeting ABL myristoyl pocket in the ABL1 protein. Methods: Forty one patients with chronic myeloid leukemia treated with asciminib from 2018 to 2022 were reviewed and analyzed for the efficacy and tolerability of asciminib using real-world experience data. Results: The median age was 60 year...

Background: Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared to the general population. We sought to evaluate the impact of mosaic chromosomal alterations (mCAs) on death of CVD causes, coronary artery disease (CAD) causes, and of any cause in patients with a cancer diagnosis. Methods: The study was a prospectiv...

Blood cell production is complex, partly genetically determined and influenced by acquired factors. However, there is a paucity of data on how these factors interplay in the context of aging, which is associated with a myeloid proliferation bias, clonal hematopoiesis (CH) and an increased incidence of myeloid cancers. We investigated hereditary and...

Background Childhood maltreatment can result in lifelong psychological and physical sequelae, including coronary artery disease (CAD). Mechanisms leading to increased risk of illness may involve emotional dysregulation and shortened leukocyte telomere length (LTL). Methods To evaluate whether (1) childhood maltreatment is associated with shorter L...

Introduction: Cancer survivors are at an increased risk for cardiovascular (CV)-related deaths. Recently, clonal hematopoiesis (CH) was described as a novel risk factor for both cancer and CV disease. However, the influence of CH on CV outcomes in cancer survivors has not been explored. Hypothesis: We hypothesized that CH captured by mosaic chromos...

Antigen-specific T cells expansion ex vivo followed by adoptive transfer enables the targeting of a multitude of microbial and cancer antigens. However, clinical scale T-cell expansion from rare precursors requires repeated stimulations which may lead to T-cell dysfunction and limited therapeutic potential. We used a clinically-compliant protocol t...

Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared to the general population. Here, we evaluated the impact of somatic mosaic chromosomal alterations (mCAs) on death of CVD causes, coronary artery disease (CAD) causes, from cancer, and of any cause in patients with a cancer diagnosis within the UK Biobank (n=48 919)....

Based on analyses of TCR sequences from over 1,000 individuals, we report that the TCR repertoire is composed of two ontogenically and functionally distinct types of TCRs. Their production is regulated by variations in thymic output and terminal deoxynucleotidyl transferase (TDT) activity. Neonatal TCRs derived from TDT-negative progenitors persist...

Acute myeloid leukemia (AML) is a cancer that originates from the bone marrow (BM). Under physiological conditions, the bone marrow supports the homeostasis of immune cells and hosts memory lymphoid cells. In this review, we summarize our present understanding of the role of the immune microenvironment on healthy bone marrow and on the development...

Individuals with age-related clonal hematopoiesis (CH) are at greater risk for hematologic malignancies and cardiovascular diseases. However, predictive preclinical animal models to recapitulate the spectrum of human CH are lacking. Through error-corrected sequencing of 56 human CH/myeloid malignancy genes we identified natural CH driver mutations...

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and pro...

Based on analyses of TCR sequences from over 1,000 individuals, we report that the TCR repertoire is composed of two ontogenically and functionally distinct types of TCRs. Their production is regulated by variations in thymic output and terminal deoxynucleotidyl transferase (TDT) activity. Neonatal TCRs derived from TDT-negative progenitors persist...

Background Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive personality traits related to coronary artery disease (CAD). The purpose of this study was to evaluate the...

Acute Central Nervous System (CNS) Graft Versus Host Disease (GvHD) is a rare form of GvHD, only described in case reports. Knowledge about this condition is extrapolated from chronic CNS GvHD cases occurring mostly after hematopoietic stem cell transplantation. GvHD following solid organ transplantation is an unexpected complication. GvHD after li...

Introduction: Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) widely used for the treatment of Philadelphia chromosome positive chronic myeloid leukemia (CML). ENESTnd, which compared two doses of nilotinib to imatinib for patients with newly diagnosed CML, demonstrated superior rates of major molecular responses (MMRs) at...

Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widel...

Introduction Hematopoiesis ensures lifelong oxygenation, immune and hemostatic functions through the production of billions of blood cells on a daily basis. However, little is known about the factors regulating and influencing this highly coordinated process and the resulting peripheral blood cell quantitative traits during the aging process. In th...

Background and methods: Increasing life expectancy has had the impact of increasing the proportion of patients with myeloproliferative neoplasms (MPN) aged ≥75 years (very elderly patients; VEP). However, few studies have evaluated the phenotype and prognostic factors specific to this population. This is a retrospective multicenter chart review (11...

Introduction: Cytoreductive therapy such as hydroxyurea and interferon is recommended for high-risk polycythemia vera (PV) patients (pts) and is often used as first-line (1L) therapy. Yet, nearly a quarter of pts discontinue 1L therapy due to resistance or intolerance, requiring second-line (2L) therapy. While ruxolitinib (RUX) is an FDA- and EMA-a...

Background: Asciminib (ASC) is a novel, first in class inhibitor specifically targeting the ABL myristate pocket. Phase 3 data comparing ASC to bosutinib have shown a higher rate of major molecular (MMR; 25.5% vs 13.2%) and complete cytogenetic response (40.8% vs 24.2%) at 6 months (mo) in CML patients (pts) in chronic phase (CP) who have failed at...

text: Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established st...

DNA methyltransferases (DNMTi), also often called hypomethylating agents (HMAs), have historically been administered parenterally due to limited and variable oral availability. • Cedazuridine is a novel, potent, and safe inhibitor of cytidine deaminase and when given in combination with decitabine, enables efficient oral availability 1 • A fixed do...

Background. The stimulation and expansion of antigen-specific T cells ex vivo enables the targeting of a multitude of cancer antigens. However, clinical scale T-cell expansion from rare precursors requires repeated stimulations ex vivo leading to T-cell terminal effector differentiation and exhaustion that adversely impact therapeutic potential. We...

The doubling time (DT) of the BCR–ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re‐growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = l...

Dasatinib is a second‐generation BCR‐ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib‐associated significant adverse events (AEs) by...

Background Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission. Methods The present study is a phase...

7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficac...

Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment‐free remission (TFR) success after TKI discontinuation, the optimal cut‐off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study....

Background Evidence suggests the role of an inflammatory storm in COVID-19 complications. Colchicine is an orally administered, anti-inflammatory medication beneficial in gout, pericarditis and coronary disease. Methods We performed a randomized, double-blind trial involving non-hospitalized patients with COVID-19 diagnosed by polymerase chain reac...

Background Evidence suggests the role of an inflammatory storm in COVID-19 complications. Colchicine is an orally administered, anti-inflammatory medication beneficial in gout, pericarditis and coronary disease. Methods We performed a randomized, double-blind trial involving non-hospitalized patients with COVID-19 diagnosed by polymerase chain reac...

Background: Several clinical factors have been proposed to predict successful tyrosine kinase inhibitor (TKI) discontinuation for treatment-free remission (TFR), among which a longer duration of total TKI or deep molecular response (DMR) duration correlate with increased success of TFR. Although many guidelines have been proposed to safely select p...

Background: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial, named "Treatment Free Remission Accomplished By Dasatinib " (NCT#02268370), has reported 56.8% molecular relapse-free survival (mRFS) rate at 12 months after imatinib (IM) discontinuation. MMR loss occurred quickly after IM discontinuation, typically within 2-4 months,...

Introduction: Hypomethylating agents (HMAs) or DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine are established standard of care for the treatment of MDS and CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver, hence requiring intravenous...

Introduction Rapid T cell reconstitution following hematopoietic stem cell transplantation is essential for protection against infections and has been associated with lower incidence of chronic graft-vs-host disease (cGVHD), relapse and transplant-related mortality (TRM). While cord blood (CB) transplants are associated with lower rates of cGVHD an...

Background: Since lowering the hemoglobin (Hb) and hematocrit (Hct) diagnostic thresholds for polycythemia vera (PV) to 165 g/L and 49% in men and 160 g/L and 48% in women respectively, by the World Health Organization (WHO) in 2016 (Blood. 2016;127:2391), hematologists have witnessed an increase in referrals for erythrocytosis, a significant propo...

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Rapid T cell reconstitution following hematopoietic stem cell transplantation (HSCT) is essential for protection against infections and has been associated with lower incidence of chronic graft-versus-host disease (cGVHD), relapse, and transplant-related mortality (TRM). While cord blood (CB) transplants are associated with lower rates of cGVHD and...

Haplo‐identical donors have been increasingly used as an alternative source of stem cells in patients with severe aplastic anemia in need of an allogeneic transplantation but lack a matched donor. Single cord blood (CB) transplant also offers a curative option for this disease, but few adult patients have been reported due to low number of progenit...

Clonal hematopoiesis of indeterminate potential (CHIP) is predictive of hematological cancers and cardiovascular diseases, but the etiology of CHIP initiation and clonal expansion is unknown. Several lines of evidence suggest that proinflammatory cytokines may favor mutated hematopoietic stem cell expansion. To investigate the potential link betwee...

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic...

Background Benefits of cord blood (CB) transplantation include low rates of relapse and chronic graft-versus-host disease (GVHD). However, CB use has rapidly declined because of the high rates of infections, severe acute GVHD, and transplant-related mortality (TRM) as well as prolonged hospitalization. We therefore initiated a clinical trial with U...

The history of clonal hematopoiesis (CH) research was punctuated by several seminal discoveries that have forged our understanding of cancer development. The clever application of the principle of random X-chromosome inactivation (XCI) in females lead to the development of the first test to identify clonal derivation of cells. Initially limited by...

Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 59.1% and 21.5% molecular relapse-free survival (RFS) rate after first attempt of treatment free remission (TFR1) with imatinib (IM) discontinuation and after a 2nd attempt of TFR (TFR2) with dasatinib (DA) discontinuation, respectively. Throughout the f...

Introduction: The Canadian trial entitled "Treatment Free Remission Accomplished By Dasatinib" (BMS CA180543, NCT#02268370) is ongoing since Jan 2015, and has completed accrual of 131 patients. The study was designed to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI dis...

Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolonged anemia, thrombocytopenia and/or leukopenia via c-kit blockade in hematopoietic stem cells. Previous studies have reported that even low-grade adverse events could impair a patient's health-related quality of life. One of the benefits of TKI discontin...

Background Benefits of cord blood (CB) transplantation include low rates of relapse and chronic graft-versus-host disease (cGVHD). However, CB use is rapidly declining because of delayed neutrophil recovery, high rates of infections and severe acute GVHD leading to high transplant-related mortality (TRM) and prolonged hospitalization. Several of th...

Background: Benefits of cord blood transplantation include low rates of relapse and chronic graft-versus-host disease (GVHD). However, the use of cord blood is rapidly declining because of the high incidence of infections, severe acute GVHD, and transplant-related mortality. UM171, a haematopoietic stem cell self-renewal agonist, has been shown to...

Graft‐versus‐host disease (GVHD) is a major cause of transplant‐related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T‐cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant...

Objective: To document the Mayo Clinic decades-long experience with myeloproliferative neoplasms (MPNs) and provide mature risk-stratified survival data and disease complication estimates. Patients and methods: All Mayo Clinic patients with World Health Organization-defined MPNs constituted the core study group and included those with polycythem...