Leukemia最新文献

Relapsed Acute Lymphoblastic Leukemia (ALL) is among the most common causes of cancer-associated deaths in children. However, little is known about the implications of deviations from ALL treatment protocols on survival rates. The present study elucidates the various characteristics of treatment deviations in children with relapsed ALL included in the ALL-REZ BFM 2002 (i.e., Relapse Berlin-Frankfurt- Münster) trial and determines their prognostic relevance for relapse and death rates. Among 687 patients, 100 were identified with treatment deviations, further classified, and examined by occurrence time, cause and type. Protocol deviation was considered a time-dependent variable and its impact on Disease Free Survival (DFS) and Overall Survival (OS) was examined using the time-dependent model Mantel Byar. Five years after the relapse diagnosis, deviations were significantly related to both inferior DFS (38%) and OS (57%) rates compared to protocol conformed treatment (DFS = 61%; OS = 70%, P < 0.001). Based on multivariate analyses, protocol deviation proved to be an independent adverse prognostic factor of DFS. Moreover, deviations triggered by chemotherapy-induced toxicity were associated with a higher relapse rate compared to deviations due to insufficient response. Therefore, to avoid impairment of results by deviations, future clinical trials, and treatment strategies should focus on less toxic treatments and stricter protocol compliance.

Richter transformation (RT) is the histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RT has devastating consequences with survival after transformation typically <1 year [1]. Estimates of RT frequency vary by study design, setting, and duration of follow-up. In several large studies from time periods when chemoimmunotherapy (CIT) was used to treat patients with CLL, RT rates have been reported between 2 and 10% after a median follow-up of 4–6 years from the time of diagnosis; these studies included patients with both newly diagnosed CLL and treated CLL [2,3,4,5,6]. Targeted therapies, including Bruton tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL2i), are now standard of care treatment for patients with CLL. High RT rates (up to 25%) reported in early studies with BTKi and BCL2i in relapsed CLL patients likely reflect increased RT risk among heavily pre-treated patients rather than risk due to these therapies themselves [7, 8]. Comparison of risk after specific treatment exposures from first-line clinical trials with CIT and targeted therapy arms is limited by the low numbers of RT events reported [9,10,11,12,13]. As the treatment paradigm for CLL has changed and CLL patients are living longer, we aimed to assess the current risk of developing RT and the potential impact of targeted therapies on that risk by comparing cohorts of patients with newly diagnosed CLL across different time periods.

Following IRB approval, we identified patients with previously untreated CLL in the Mayo Clinic CLL Database who were seen within 12 months of diagnosis. Only cases of biopsy proven DLBCL with histopathologic confirmation at Mayo Clinic were considered an RT event. Cumulative incidence methodology was used to display the time to development of RT, both from time of initial CLL diagnosis and from start of CLL-directed therapy, with death as a competing risk. We defined the period prior to February 2014 (FDA approval of ibrutinib for CLL) as the pre-targeted therapy era and the period after February 2014 as the targeted therapy era. Using Cox proportional hazards regression analysis, we compared the incidence of RT between patients diagnosed with CLL in the pre-targeted therapy era versus the targeted therapy era. Cox regression analysis was also used to investigate the association of effects of type of treatment exposure (time-dependent variable) on risk of RT. Statistical analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC, USA).

Whether there is really a distinct accelerated phase (AP) at diagnosis in chronic myeloid leukaemia (CML) in the context of tyrosine kinase-inhibitor (TKI)-therapy is controversial. We studied 2122 consecutive subjects in chronic phase (CP, n = 1837) or AP (n = 285) at diagnosis classified according to the 2020 European LeukemiaNet (ELN) classification. AP subjects with increased basophils only had similar transformation-free survival (TFS) and survival compared with CP subjects classified as ELTS intermediate-risk. Those with increased blasts only had worse TFS but similar survival compared with CP subjects classified as ELTS high-risk. AP subjects with decreased platelets only had similar TFS but worse survival compared with subjects classified as ELTS high-risk. Proportions of CP and AP subjects meeting the 2020 ELN TKI-response milestones were similar. However, worse TFS at 3-month and survival at 6- or 12-month were only in AP subjects failing to meet ELN milestones. Findings were similar using the 2022 International Consensus Classification (ICC) criteria for AP replacing decreased platelets with additional cytogenetic abnormalities. Our data support the 2022 WHO classification of CML eliminating AP. We suggest adding a very high-risk cohort to the ELTS score including people with increased blasts or decreased platelets and dividing CML into 2 phases at diagnosis: CP and acute or blast phases.

KMT2A::MLLT3 acute myelomonocytic leukemia (AML) comes in two clinically and biologically different subtypes. One is characterized by inferior outcome, older age, and MECOM oncogene expression. The other is mainly observed in children and young adults, associates with better clinical outcome, but lacks MECOM. To identify cell fate determining transcription factors downstream of KMT2A::MLLT3, we applied a bioinformatic algorithm that integrates gene and enhancer expression from primary MECOM-positive and -negative KMT2A::MLLT3 AML samples. This identified MECOM to be most influential in the MECOM-positive group, while neuronal transcription factor HMX3 was most influential in the MECOM-negative group. In large AML cohorts, HMX3 expression associated with a unique gene expression profile, younger age (p < 0.002) and KMT2A-rearranged and KAT6A-CREBBP leukemia (p < 0.00001). HMX3 was not expressed in other major genetic risk groups and healthy blood cells. RNA-sequencing analyses following forced HMX3 expression in healthy CD34+ cells and its silencing in KMT2A::MLT3 cells showed that HMX3 drives cancer-associated E2F and MYC gene programs (p < 0.001). HMX3 expression in healthy CD34+ cells blocked monocytic but not granulocytic colony formation. Strikingly, HMX3 silencing in KMT2A::MLLT3 patient cells resulted in cell cycle arrest, monocytic differentiation and apoptosis. Thus, the neuronal transcription factor HMX3 is a leukemia-specific vulnerability in KMT2A::MLLT3 AML.