Hepatitis C virus (HCV) chronic infection can be associated with extrahepatic manifestations such as mixed cryoglobulinaemia and lymphoproliferative disorders that are endowed with increased rates of morbidity and all-cause mortality. In this study, we used flow cytometry to evaluate the effect of interferon-free antiviral treatment on peripheral blood lymphocytes in HCV-infected patients with or without associated lymphoproliferative disorders. Flow cytometry analysis of peripheral blood lymphocytes was performed at baseline and at the end of treatment. In HCV-infected patients with lymphoproliferative disorders, we evaluated immunoglobulin (Ig) light chain κ/λ ratio variations as a measure of monoclonal B-cell response to antiviral therapy. Healthy volunteers were enrolled as controls. A total of 29 patients were included, nine with and 20 without lymphoproliferative disorders. Sustained virological response was achieved in 29 of 29 patients. We observed a significant reduction in the B-cell compartment (39% global reduction) in eight of nine HCV-infected patients with lymphoproliferative disorders after viral clearance. We recognized the same trend, even if less pronounced, in HCV-infected patients without lymphoproliferative disorders (9% global reduction). Among HCV-infected patients with lymphoproliferative disorders, three showed an improvement/normalization of the immunoglobulin light chain ratio, whereas in the remaining six patients monoclonal B cells persisted to be clonally restricted even 1 year after the end of treatment. Our data show that DAAs treatment can be effective in reducing the frequency of pathological B cells in the peripheral blood of HCV-infected patients affected by HCV-associated lymphoproliferative disorders; however, monoclonal populations can persist after viral eradication.

Fraction of GF is useful to identify subjects at high risk for early death and therefore in need of early treatment.

Peripheral neuropathy is a common complication of arsenic toxicity. Symptoms are usually mild and reversible following discontinuation of treatment. A more severe chronic sensorimotor polyneuropathy characterized by distal axonal-loss neuropathy can be seen in chronic arsenic exposure. The clinical course of arsenic neurotoxicity in patients with coexistence of thiamine deficiency is only anecdotally known but this association may potentially lead to severe consequences.We describe a case of acute irreversible axonal neuropathy in a patient with hidden thiamine deficiency who was treated with a short course of arsenic trioxide for acute promyelocytic leukemia. Thiamine replacement therapy and arsenic trioxide discontinuation were not followed by neurological recovery and severe polyneuropathy persisted at 12-month follow-up.Thiamine plasma levels should be measured in patients who are candidate to arsenic trioxide therapy. Prophylactic administration of vitamin B1 may be advisable. The appearance of polyneuropathy signs early during the administration of arsenic trioxide should prompt electrodiagnostic testing to rule out a pattern of axonal neuropathy which would need immediate discontinuation of arsenic trioxide.

not in the primary sample. We also identified a ZEB2 p.R524G variant in both samples as one of the potential putative driver mutations. ZEB2 has been implicated to have crucial role in hematopoietic stem cell differentiation, mobilization, and homing [3]. Conditional overexpression of ZEB2 in mice has been reported to induce T-cell leukemia and deleterious mutations of ZEB2 have been identified in other leukemias [4,5], further suggesting the possible association between altered ZEB2 function and leukemogenesis. These are consistent with ZEB2 being a likely driver mutation in this case. The PCR capillary electrophoresis (PCR-CE) assay detected an NPM1 p.W288fs and several different sizes of FLT3-ITD in both samples (Supporting Information table).We next inferred a model of clonal evolution by tracing cancer cell fraction (CCF) of the detected variants (Fig. 1). Both primary and relapse AML shared the same founder clone with IDH1, ZEB2, and most likely the NPM1 mutation. Although the method of variant allelic fraction (VAF) calculation is different between WES and PCR-CE, VAF of NPM1 mutation on PCR-CE was stable around 0.5. Further, a previous study has shown that NPM1 mutation is almost always an early founding event in AML, consistent with the NPM1 mutation as early clonal event in this case. We did not incorporate FLT3-ITD into our model because association between respective ITD sizes and clonality has not been well understood. However, as a whole, FLT3-ITD was clearly detected at two time points, suggesting that this mutation persisted in the dominant clone.Our model suggests that the founder clone persisted after initial therapy and relapsed 19 years later with additional mutations acquired. Overall, it is consistent with one of the models that were proposed by Ding et al., who performed whole genome sequencing on eight relapsed AML cases, all of which relapsed within 3 years of remission [6]. Our report differs in that our case had a larger fraction of relapse-specific mutations and fewer shared mutations between primary and relapse AML. This would be consistent with the much longer period before relapse and accumulation of additional mutations over this time period.We also observed the emergence of a minor population with an SF3B1 mutation at relapse. CCF of the SF3B1 mutation did not follow that of the founder clone after salvage therapy (Fig. 1). SF3B1 mutation is frequently associated with MDS but rare in AML. The studied patient was suspected to have MDS 3 years before she experienced relapse (Supporting Information Appendix). Taken together, it is likely that the clone with SF3B1 mutation represents the co-occurrence of MDS in the context of a relapsing AML.In summary, longitudinal genomic characterization of an individual with a late relapse of AML revealed that the founder clone of the primary AML persisted after treatment and constituted the basis of relapsed disease 19 years later, hence confirming "true" relapse. More cases of late relapse in AML need to be examined to better characterize the m...

We performed a registry study on therapy-related myeloid neoplasm (t-MN), both therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) following treatment for breast cancer who underwent a first allogeneic hematopoietic cell transplant (allo-HCT). Of 252 identified female patients (median age 57 years), 77% were transplanted for t-AML and 23% for t-MDS, with a median time from breast cancer diagnosis to the diagnosis of tMN and subsequent allo-HCT of 3.7 and 4.6 years, respectively. At transplant, 191 patients were in remission for breast cancer, while 4 were not (57 missing). T-MN was in a complete remission at the time of transplant in 67% of patients. 2-year overall survival, relapse free-survival, relapse incidence and nonrelapse mortality were 50%, 45%, 33%, and 22%, respectively. Multivariable analysis revealed that if the t-MN was not in CR pretransplant, this was associated with lower OS, RFS, and a higher relapse incidence. Seventeen cases of breast cancer recurrence were recorded after a median of 2.4 years post-transplant, and relapse of primary breast cancer accounted for 7% of deaths. This study indicates that allo-HCT for t-MN following treatment for breast cancer shows encouraging transplant outcomes. The incidence of breast cancer relapse post-transplant remains a cause for concern.