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Summary: This study compared decitabine exposure when administered IV (DEC‐IV) at a dose of 20 mg/m2 for 5‐days with orally administered decitabine with cedazuridine (DEC‐C), as well as the clinical efficacy and safety of DEC‐C in patients with acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy. In all, 89 patients were randomised 1:1 to DEC‐IV or oral DEC‐C (days 1–5 in a 28‐day treatment cycle), followed by 5 days of the other formulation in the next treatment cycle. All patients received oral DEC‐C for subsequent treatment cycles until treatment discontinuation. Equivalent systemic decitabine exposures were demonstrated (5‐day area under the curve ratio between the two decitabine formulations of 99.64 [90% confidence interval 91.23%, 108.80%]). Demethylation rates also were similar (≤1.1% difference). Median overall survival (OS), clinical response and safety profile with oral DEC‐C were consistent with those previously observed with DEC‐IV. Next‐generation sequencing was performed to identify molecular abnormalities that impact OS and TP53 mutations were associated with a poor outcome. These findings support the use of oral DEC‐C in patients with AML. [ABSTRACT FROM AUTHOR]

Summary: Induction therapy followed by CD34+ cell mobilisation and autologous transplantation represents standard of care for multiple myeloma (MM). However, the anti‐CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. In this study, we investigated the effect of three different regimens (dara‐VCd, isa‐KRd and VTd) on CD34+ cells using flow cytometry and transcriptomics. Decreased CD34+ cell peak concentration and yields, longer collection and delayed engraftment were reproduced after dara‐VCd/isa‐KRd versus VTd induction in 34 patients in total. Using flow cytometry, we detected major changes in the proportion of apheresis product and bone marrow CD34+ subsets in patients treated with regimens containing anti‐CD38 therapy; however, without any decrease in CD38high B‐lymphoid progenitors in both materials. RNA‐seq of mobilised CD34+ cells from 21 patients showed that adhesion genes are overexpressed in CD34+ cells after dara‐VCd/isa‐KRd and JCAD, NRP2, MDK, ITGA3 and CLEC3B were identified as potential target genes. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion‐related interactions, rather than killing of CD34+ cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti‐CD38 therapy. [ABSTRACT FROM AUTHOR]

Introduction. Immunoablative therapy followed by autologous hematopoietic stem cell transplantation (AHSCT) is one of the possible disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS). In this case series, we would like to present six patients with MS, who underwent AHSCT as the first-line DMT. Case reports. Six MS patients with a rapid progression of disability with or without relapses underwent AHSCT as the first-line DMT at the University Hospital Ostrava between 2018 and 2021. The conditioning regimens for AHSCT used were a medium-intensity regime BEAM (Carmustine, Etoposid, Cytarabin, Melphalan) and low-intensity regime based on Cyclophosphamide. Four out of six patients showed some disability progression after AHSCT, so the rapid progression of MS was just slowed down by AHSCT. One patient developed activity on magnetic resonance imaging three months after AHSCT, and two experienced mild relapses during the follow-up period. None of our patients developed grade 4 non-hematological toxicity; all infections were mild. In one patient, an allergic reaction probably to dimethyl sulfoxide was observed. Conclusion. Our case series of 6 patients shows that AHSCT is a promising therapeutic approach to slow down the rapid progression of clinical disability in MS patients with a good safety profile. [ABSTRACT FROM AUTHOR]

Induction therapy followed by CD34 + cell mobilisation and autologous transplantation represents standard of care for multiple myeloma (MM). However, the anti-CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. In this study, we investigated the effect of three different regimens (dara-VCd, isa-KRd and VTd) on CD34 + cells using flow cytometry and transcriptomics. Decreased CD34 + cell peak concentration and yields, longer collection and delayed engraftment were reproduced after dara-VCd/isa-KRd versus VTd induction in 34 patients in total. Using flow cytometry, we detected major changes in the proportion of apheresis product and bone marrow CD34 + subsets in patients treated with regimens containing anti-CD38 therapy; however, without any decrease in CD38high B-lymphoid progenitors in both materials. RNA-seq of mobilised CD34 + cells from 21 patients showed that adhesion genes are overexpressed in CD34 + cells after dara-VCd/isa-KRd and JCAD, NRP2, MDK, ITGA3 and CLEC3B were identified as potential target genes. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion-related interactions, rather than killing of CD34 + cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti-CD38 therapy., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Plerixafor can rescue the outcome of failing chemotherapy-based stem cell mobilization. However, the optimal time for plerixafor injection in this setting has not been determined. This was investigated by retrospective analysis of data from 48 mobilizations with plerixafor, chemotherapy, and granulocyte-colony stimulating factor (G-CSF). The required yield of 2.0 × 10(6) CD34+ cells/kg was collected from 71% of patients; the median total yield was 4.1 × 10(6) CD34+ cells/kg. Patients to whom plerixafor was administered late (≥ 15 days) after chemotherapy, after a long duration (≥ 13 days) of treatment with G-CSF, or when the white blood cell count was high (≥ 20 × 10(9)/L) were mobilized as efficiently as other patients. Plerixafor was shown to rescue mobilizations at a comparable rate in patients with critically low levels of peripheral blood CD34+ cells (<3/µL) and those with higher concentrations. These data suggest that late administration of plerixafor in the course of chemotherapy-based mobilization does not contribute to the failure of this strategy.

We show that common heterochromatin antigenic protein markers [HP1alpha, -beta, -gamma and mono-, di-, and trimethylated histone H3 lysine 9 (H3K9)], although present in human blood progenitor CD34+ cells, differentiated lymphocytes, and monocytes, are absent in neutrophil granulocytes and to large extent, in eosinophils. Monomethylated and in particular, dimethylated H3K9 are present to variable degrees in the granulocytes of chronic myeloid leukemia (CML) patients, without being accompanied by HP1 proteins. In patients with an acute phase of CML and in acute myeloid leukemia patients, strong methylation of H3K9 and all isoforms of HP1 are detected. In chronic forms of CML, no strong correlations among the level of histone methylation, disease progression, and modality of treatment were observed. Histone methylation was found even in "cured" patients without Philadelphia chromosome (Ph) resulting from +(9;22)(q34;q11) BCR/ABL translocation, suggesting an incomplete process of developmentally regulated chromatin remodeling in the granulocytes of these patients. Similarly, reprogramming of leukemia HL-60 cells to terminal differentiation by retinoic acid does not eliminate H3K9 methylation and the presence of HP1 isoforms from differentiated granulocytes. Thus, our study shows for the first time that histone H3 methylation may be changed dramatically during normal cell differentiation. The residual histone H3 methylation in myeloid leukemia cells suggests an incomplete chromatin condensation that may be linked to the leukemia cell proliferation and may be important for the prognosis of disease treatment and relapse.