Combined Proteasome and Autophagy Inhibition in Relapsed/Refractory Multiple Myeloma-A Phase I Trial of Hydroxychloroquine, Carfilzomib, and Dexamethasone.

Multiple myeloma is characterized by malignant cells which produce high amounts of monoclonal immunoglobulin. Myeloma cells are, therefore, dependent on effective protein degradation. Proteasomal protein degradation is targeted by proteasome inhibitors in routine care.

High-throughput drug screening identifies SMAC mimetics as enhancers of NK cell cytotoxicity in chronic myeloid leukemia.

Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK cell function with oncological drugs could improve NK cell-based immunotherapies. Here, we used a high-throughput drug screen consisting of over 500 small-molecule compounds to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells.

Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response.

The advent of tyrosine kinase inhibitors (TKIs) as treatment of chronic myeloid leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI-insensitive leukemia stem cells (LSCs) persist in most patients even after years of treatment and are imperative for disease progression as well as recurrence during treatment-free remission (TFR). Here, we have generated high-resolution single-cell multiomics maps from CML patients at diagnosis, retrospectively stratified by BCR::ABL1 (%) following 12 months of TKI therapy.

Health-related quality of life and symptoms of chronic myeloid leukemia patients after discontinuation of tyrosine kinase inhibitors: results from the EURO-SKI Trial.

Limited data is available on the health-related quality of life (HRQoL) and symptoms of patients with chronic myeloid leukemia (CML) who are in treatment-free remission (TFR). We herein report HRQoL results from the EURO-SKI trial. Patients who had been on tyrosine kinase inhibitors (TKIs) therapy for at least 3 years and achieved MR4 for at least 1 year were enrolled from 11 European countries, and the EORTC QLQ-C30 and the FACIT-Fatigue questionnaires were used to assess HRQoL and fatigue respectively.

The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib.

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response.

Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation.

Immunological control of residual leukemia cells is thought to occur in patients with chronic myeloid leukemia (CML) that maintain treatment-free remission (TFR) following tyrosine kinase inhibitor (TKI) discontinuation. To study this, we analyzed 55 single-cell RNA and T cell receptor (TCR) sequenced samples (scRNA+TCRαβ-seq) from patients with CML (n = 13, N = 25), other cancers (n = 28), and healthy (n = 7). The high number and active phenotype of natural killer (NK) cells in CML separated them from healthy and other cancers.

Switching from imatinib to nilotinib plus pegylated interferon-α2b in chronic phase CML failing to achieve deep molecular response: clinical and immunological effects.

In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response <0.01% BCR-ABL1 (MR) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR at month 12 (a BCR-ABL1 level ≤ 0.

IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia.

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-α in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCRβ sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples).

Long-term tolerability and efficacy after initial PegIFN-α addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study.

Objectives: Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-α in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations.

Cold agglutinin disease revisited: a multinational, observational study of 232 patients.

We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR).

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants.

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies.

Plasma proteomics of biomarkers for inflammation or cancer cannot predict relapse in chronic myeloid leukaemia patients stopping tyrosine kinase inhibitor therapy.

Several studies have now shown that chronic myeloid leukaemia (CML) patients in deep molecular remission may discontinue tyrosine kinase inhibitor (TKI) treatment with a treatment free remission (TFR) rate of approximately 40-60 %. Some factors influencing the possibility of TFR have been described but better tools are needed for individual prediction of long-term TFR. Herein, two multiplex panels were utilised to analyse a total of 162 different plasma proteins from 56 patients included in the TKI stopping trial EURO-SKI (Saussele et al.

Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line.

Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557).

Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia.

Telomere length (TL) in peripheral blood (PB) cells of patients with chronic myeloid leukemia (CML) has been shown to correlate with disease stage, prognostic scores, response to therapy, and disease progression. However, due to considerable genetic interindividual variability, TL varies substantially between individuals, limiting its use as a robust prognostic marker in individual patients. Here, we compared TL of BCR-ABL, nonleukemic CD34CD38 hematopoietic stem cells (HSC) in the bone marrow of CML patients at diagnosis to their individual BCR-ABL leukemic stem cell (LSC) counterparts.

Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial.

Background: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment.

CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting.

Tyrosine kinase inhibitors (TKIs) are highly effective for the treatment of chronic myeloid leukemia (CML), but very few patients are cured. The major drawbacks regarding TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon drug cessation. Herein, we performed ribonucleic acid sequencing of flow-sorted primitive (CD34CD38) and progenitor (CD34 CD38) chronic phase CML cells, and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells.