[Show abstract][Hide abstract] ABSTRACT: Patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) often have constant minor side-effects which have a significant impact on their daily lives and on their adherence to prescribed medication. One possible strategy to minimize these side effects is to take advantage of low cross intolerance between different TKIs and to “proactively” change therapy. However it is not clear whether such a change can adversely affect response, induce resistance or indeed eliminate a given side effect. In this work we describe outcomes in 57 patients who after attaining complete cytogenetic response changed from imatinib to a second generation TKI solely due to persistent minor side effects. After one or more changes of therapy 46 of the 57 patients were entirely free of side effects and an additional 11 patients had nearly complete resolution of side effects resulting in total or almost complete absence of minor persistent side effects in all cases. Furthermore all patients improved their levels of molecular response and BCR-ABL1 kinase mutations were not detected in any patient after change of therapy. Proactively changing therapy on account of persistent minor side effects seems to be an effective and safe therapeutic option for CML patients.
[Show abstract][Hide abstract] ABSTRACT: Haemophilia B, resulting from a deficiency of coagulation factor IX (FIX), is treated effectively by either recombinant (r) or plasma derived (pd) FIX concentrates although differences in pharmacokinetics are observed. FIX is activated in vivo by both FXIa and tissue factor (TF)-FVIIa, however conventional APTT-based assays assess only activation by FXIa.
To examine the differences between pd-FIX and r-FIX concentrates with respect to their thrombogenicity and activation.
FIX ELISA was used to quantify antigenic FIX. Calibrated automated thrombography (CAT) was performed to evaluate the effect of FIX on thrombin generation. FIXa was quantified by the cleavage of FIXa specific chromogenic substrate. FIX activation was studied in a purified system.
We found that r-FIX had ~1.6 fold greater specific activity than pdFIX. r-FIX generated a markedly higher thrombin peak compared to pd-FIX at equivalent antigen level when coagulation was initiated by TF, which was not seen in contact activation-triggered thrombin generation (TG). Interestingly, FIXa contained in r-FIX was 10 times higher than in pd concentrate. In a purified system, the amount of r-FIXa generated by FXIa in the first 10 minutes of activation was 1.37x that of pd-FIXa, whereas no difference was observed when triggered by TF/FVIIa.
Clear differences are observed between pd-FIX and r-FIX concentrates including the proportion of FIXa and the activation by FXIa. These may explain some of the discrepancies observed clinically and suggest that the APTT may not reflect their resultant in vivo properties. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Transient Abnormal Myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood Acute Myeloid Leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM neither specify % blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195/200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/Denaturing High Performance Liquid Chromatography (Ss/DHPLC) in 17/200 (8.5%); all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation-resequencing (NGS) in 18/88 (20.4%)(sensitivity ~0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term Silent TAM for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation analysis, blood counts and smears, should be performed in DS neonates. Ss/DPHLC can be used for initial screening but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones.
[Show abstract][Hide abstract] ABSTRACT: The high frequency of a unique neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM), and subsequent acute myeloid leukaemia in early childhood in patients with trisomy 21 (Down syndrome) points to a specific role for trisomy 21 in transforming foetal haematopoietic cells. N-terminal truncating mutations in the key haematopoietic transcription factor GATA1 are acquired during foetal life in virtually every case. These mutations are not leukaemogenic in the absence of trisomy 21. In mouse models, deregulated expression of chromosome 21-encoded genes is implicated in leukaemic transformation, but does not recapitulate the effects of trisomy 21 in a human context. Recent work using primary human foetal liver and bone marrow cells, human embryonic stem cells and iPS cells shows that prior to acquisition of GATA1 mutations, trisomy 21 itself alters human foetal haematopoietic stem cell and progenitor cell biology causing multiple abnormalities in myelopoiesis and B-lymphopoiesis. The molecular basis by which trisomy 21 exerts these effects is likely to be extremely complex, to be tissue-specific and lineage-specific and to be dependent on ontogeny-related characteristics of the foetal microenvironment.
[Show abstract][Hide abstract] ABSTRACT: Tyrosine kinase inhibitors (TKI) have significant off-target multi-kinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase CML patients on imatinib, or second-line dasatinib and nilotinib and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared to controls (IgM titer 79.0 vs. 200 U/ml, p=0.0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B-cells. In vitro co-incubation of B-cells with plasma from CML patients on TKI or with imatinib, dasatinib or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B cell signaling and survival. These data indicate that TKI, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.
[Show abstract][Hide abstract] ABSTRACT: Outcomes and prognostic factors of reduced intensity-conditioned allo-SCT (RIC allo-SCT) for multiple myeloma (MM) relapsing or progressing after prior autologous (auto)-SCT are not well defined. We performed an analysis of 413 MM patients who received a related or unrelated RIC allo-SCT for the treatment of relapse/progression after prior auto-SCT. Median age at RIC allo-SCT was 54.1 years, and 44.6% of patients had undergone two or more prior auto-SCTs. Median OS and PFS from the time of RIC allo-SCT for the entire population were 24.7 and 9.6 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was 21.5%. In multivariate analysis, CMV seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior auto-SCT was associated with better OS, and shorter time from the first auto-SCT to the RIC allo-SCT was associated with lower NRM. The results of this study identify patient and donor CMV seronegativity as the key prognostic factor for outcome after RIC allo-SCT for MM relapsing or progressing after prior auto-SCT.Bone Marrow Transplantation advance online publication, 27 May 2013; doi:10.1038/bmt.2013.73.
Bone marrow transplantation 05/2013;
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