Eshrak Al-Shaibani

Tyrosine kinase inhibitors (TKIs) added to chemotherapy have improved outcomes of adult patients with Philadelphia-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). These improvements initially led to a larger proportion of patients realizing allogeneic stem cell transplantation (alloSCT), long considered essential for cure, but there has been a re-evaluation of alloSCT. At Princess Margaret Hospital (PM), adult patients with Ph+ B-ALL have been treated with a pediatric-inspired chemotherapy protocol with mostly imatinib. In the last two decades, we have witnessed many iterative changes in our approach. Here, we examine the outcomes of all Ph+ B-ALL patients treated at our institution from 2001 to 2019. During this time, there were two major protocol changes—omission of asparaginase in 2009 and discontinuation of routine referral for first complete remission (CR1) alloSCT from the early 2010s. Median follow-up was 41.13 months (range, 0.46–228.79). In total, 141 patients (91.56%) achieved CR1. Patient outcomes improved iteratively, with the best results seen in the final (2016–2019) cohort: no asparaginase, no routine alloSCT referral in CR1; 4-year overall survival (OS) and relapse-free survival (RFS) were 87.0% and 69.3%, respectively. The long-term OS in this patient group retained statistical significance in the multivariable analysis (p = 0.0176) when BCR::ABL1 molecular measurable residual disease (MRD) was considered.

Tyrosine kinase inhibitors (TKIs) added to chemotherapy have improved outcomes ofadult patients with Philadelphia-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). These improvements initially led to a larger proportion of patients realizing allogeneic stem cell transplantation (alloSCT), long considered essential for cure, but there has been a re-evaluation of alloSCT. At Princess Margaret Hospital (PM), adult patients with Ph+ B-ALL have been treated with a pediatric-inspired chemotherapy protocol with mostly imatinib. In the last two decades, we have witnessed many iterative changes in our approach. Here we examine the outcomes of all Ph+ B-ALL patients treated at our institution from 2001 to 2019. During this time, there were two major protocol changes – omission of asparaginase in 2009, and discontinuation of routine referral for first complete remission (CR1) alloSCT from the early 2010s. Median follow-up was 41.13 months (range, 0.46-228.79). 141 patients (91.56%) achieved CR1. Patient outcomes improved iteratively, with best results seen in the final (2016-2019) cohort: no asparaginase, no routine alloSCT referral in CR1; 4-year OS and RFS were 87.0% and 69.3%, respectively. The long-term OS in this patient group retained statistical significance in the multivariable analysis (p=0.0176) when BCR::ABL1 molecular residual disease (MRD) were considered.

Tyrosine kinase inhibitors (TKIs) significantly improved outcomes for patients with chronic myeloid leukemia (CML), enabling optimal treatment responses and near-normal life expectancy. Despite optimal responses, clonal evolution (CE) in Philadelphia chromosome-negative (Ph-negative) cells occurs in 10–15% of optimal responders, typically detected via cytogenetics. The mutational dynamics underlying this phenomenon remain poorly understood. This study investigated mutational kinetics using targeted next-generation sequencing (NGS) of 40 leukemia-associated genes. A total of 119 serial peripheral blood samples from 51 newly diagnosed chronic-phase CML patients, with over 12 months of follow-up, were analyzed using single-molecule molecular inversion probe (smMIP)-based NGS. Remarkably, 24% of patients developed new somatic mutations during follow up, primarily in DNMT3a , TET2 and ASXL1. These mutations were absent at diagnosis and exhibited a median doubling time of 68 days. Notably, these mutations emerged despite patients maintaining deep molecular responses and without evidence for cytogenetic evolution. Our results highlight an ongoing clonal evolution in the Ph-negative clone suggesting the potential utility of longitudinal NGS every 6–7 months as an alternative to cytogenetic monitoring in CML.

Background.: Despite decades of post–allogeneic hematopoietic cell transplantation (HCT) growth factor utilization, its role remains undefined, leading to ongoing debates and research. The theoretical impacts of growth factors have been challenged in numerous studies. Methods.: In this retrospective cohort study conducted at the Princess Margaret Cancer Centre, we analyzed the clinical outcomes of 509 patients who underwent allogeneic HCT between May 1, 2019, and May 31, 2022. This study aimed to assess the impact of granulocyte colony-stimulating factor (G-CSF) administration posttransplantation on neutrophil and platelet engraftment, incidence of bloodstream infections (BSIs), graft-versus-host disease, engraftment syndrome (ES), and survival metrics including overall survival, nonrelapse mortality, and graft-versus-host disease–free/relapse-free survival. Results.: Our findings indicate that G-CSF administration expedited neutrophil engraftment (16 versus 18 d, P = 0.009) and was associated with a decreased incidence of BSI (9.4% versus 31.3%, P = 0.014). However, this benefit was counterbalanced by a significant delay in platelet engraftment (21 versus 17 d, P < 0.001). Multivariate logistic regression analysis identified mismatched donors (odds ratio, 1.72; 95% confidence interval, 1.03-2.88; P = 0.038) and the duration of G-CSF therapy (odds ratio, 1.04; 95% confidence interval, 1.00-1.09; P = 0.038) as independent predictors for the development of ES. Despite these hematological impacts, there was no observed advantage in overall survival, nonrelapse mortality, or graft-versus-host disease–free/relapse-free survival among patients who received G-CSF compared with those who did not. Conclusions.: Although G-CSF post-HCT expedited neutrophil engraftment and reduced BSI risk, it did not result in a survival advantage. The association with ES necessitates careful consideration.