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    • br Discussion Valproic acid is a potent inhibitor

    2019-06-05


    Discussion Valproic retinoic acid receptor is a potent inhibitor of histone deacetylases (HDAC). It can modify the structure of chromatin allowing recruitment of transcription factors to restore epigenetically suppressed genes. Valproic acid has been shown to possess antiproliferative activity and to overcome the differentiation block in leukemia blast cells. Valproic acid concentrations consistent with normal clinical dosage are believed to achieve the inhibition of HDAC. In 2004 Kuendgen et al. observed a response, according to international working group (IWG) criteria, in 8 patients (both high-risk MDS and AML) (44%) on Valproic acid monotherapy, including 1 partial remission and median response duration was 4 months (range 3–9 months). Later on, the same group confirmed their results in the same setting of patients and found that all trans retinoic acid (ATRA) could add some benefits in valproic acid nonresponders. Almost the same observations were made by an Italian group in 2005; they observed a clinical benefit in 30% of their patients (high-risk MDS and AML) treated with a combination of both valproic acid and ATRA. The association HDAC inhibitors and hypomethylating agents was also used in IPSS high risk MDS and in AML patients and 30% of patients obtained a remission (complete and partial) retinoic acid receptor suggesting, according to the authors, that valproic acid could enhance azacitidine efficacy. The same drug association was used by a German group and confirmed the results shown by Voso et al..
    Case series Despite the indisputable success of tyrosine kinase inhibitors for chronic myeloid leukaemia (CML), there remains a subset of patients for whom haematopoietic stem cell transplantation (HSCT) remains necessary. A recent follow up of the International Randomised Study of Interferon and STI571 (IRIS) Study identified that almost 30% of patients discontinued imatinib because of suboptimal response or poor tolerance of therapy. Furthermore, we know that patients presenting with advanced phase CML respond poorly to TKIs. Data on imatinib use pre-transplant has not shown any deleterious effect but data on second generation TKIs is sparse. Although CML is exquisitely sensitive to the graft-versus leukaemia (GVL) effect of HSCT, toxicity of this procedure remains a concern. A further concern is the likelihood of HSCT success in patients who have failed successive targeted therapies and have potentially acquired more resistant disease. We report our single centre experience of the impact of second generation TKIs on the outcomes of allogeneic HSCT for CML, and compare these outcomes to our previously published historic controls. Between March 2006 and December 2011, 9 patients with imatinib-resistant CML were treated with allogeneic HSCT following second generation TKI at the Beatson West of Scotland Cancer Centre. There were 7 males and median age at HSCT was 50 years (range 34–64 years). Four patients were in accelerated phase at diagnosis and 5 in chronic phase. Four patients had primary imatinib resistance and 5 had lost their response. Mutational analysis was positive in 1 patient (a binding site mutation not previously reported). At commencement of second generation TKI 7 patients were in chronic phase and 2 were in blast crisis. Nilotinib was used as a single agent in 1 patient, dasatinib in 4 patients; with sequential dasatanib and nilotinib use in 4 patients. The best response to second generation TKI was complete cytogenetic response (CCyR) in 5 patients, partial cytogenetic response (PCyR) in 1 and a complete haematological response (CHR) in 3 patients. These best responses were not all sustained at the time of HSCT (see Table 1). The median time on second generation TKI was 7 months (range 4–28 months) and in the majority of patients the TKI was stopped 2 weeks prior to HSCT. Conditioning was myeloablative in 5 patients and conditioning regimes varied according to patients\' age and suitability for myeloablative or reduced intensity regimens. For patients receiving reduced intensity regimens with a history of lymphoid blast crisis busulphan was used instead of melphalan. Graft versus host disease prophylaxis was with cyclosporin (2.5mg/kg day −2, 1.25mg/kg day −1 and levels maintained at 200–300mcg/l until dose reduction) and methotrexate 10mg/m2 on day +1, +3 and +6. In all peripheral blood stem cell grafts were used. Patient characteristics are summarised in Table 1.