Therapeutic use of valproic acid and all-trans retinoic acid in acute myeloid leukemia—literature review and discussion of possible use in relapse after allogeneic stem cell transplantation

Even though allogeneic stem cell transplantation is the most intensive treatment for acute myeloid leukemia (AML), chemo-resistant leukemia relapse is still one of the most common causes of death for these patients, as is transplant-related mortality, i.e., graft versus host disease, infections, and organ damage. These relapse patients are not always candidates for additional intensive therapy or re-transplantation, and many of them have decreased quality of life and shortened expected survival. The efficiency of azacitidine for treatment of posttransplant AML relapse has been documented in several clinical trials. Valproic acid is an antiepileptic fatty acid that exerts antileukemic activity through histone deacetylase inhibition. The combination of valproic acid and all-trans retinoic acid (ATRA) is well tolerated even by unfit or elderly AML patients, and low-toxicity chemotherapy (e.g., azacitidine) can be added to this combination. The triple combination of azacitidine, valproic acid, and ATRA may therefore represent a low-intensity and low-toxicity alternative for these patients. In the present review, we review and discuss the general experience with valproic acid/ATRA in AML therapy and we discuss its possible use in low-intensity/toxicity treatment of post-allotransplant AML relapse. Our discussion is further illustrated by four case reports where combined treatments with sequential azacitidine/hydroxyurea, valproic acid, and ATRA were used.publishedVersio

Carfilzomib and dexamethasone maintenance following salvage ASCT in multiple myeloma: A randomised phase 2 trial by the Nordic Myeloma Study Group

Objective: We investigated the efficacy and safety of carfilzomib-containing induction before salvage high-dose melphalan with autologous stem-cell transplantation (salvage ASCT) and maintenance with carfilzomib and dexamethasone after salvage ASCT in multiple myeloma.Methods: This randomised, open-label, phase 2 trial included patients with first relapse of multiple myeloma after upfront ASCT who were re-induced with four cycles of carfilzomib, cyclophosphamide and dexamethasone. Two months after salvage, ASCT patients were randomised to either observation or maintenance therapy with iv carfilzomib 27 -> 56 mg/sqm and p.o. dexamethasone 20 mg every second week. The study enrolled 200 patients of which 168 were randomised to either maintenance with carfilzomib and dexamethasone (n = 82) or observation (n = 86).Results: Median time to progression (TTP) after randomisation was 25.1 months (22.5-NR) in the carfilzomib-dexamethasone maintenance group and 16.7 months (14.4-21.8) in the control group (HR 0.46, 95% CI 0.30-0.71; P = .0004). The most common adverse events during maintenance were thrombocytopenia, anaemia, hypertension, dyspnoea and bacterial infections.Conclusion: In summary, maintenance therapy with carfilzomib and dexamethasone after salvage ASCT prolonged TTP with 8 months. The maintenance treatment was in general well-tolerated with manageable toxicity.</p

The combination of valproic acid, all-trans retinoic acid and low-dose cytarabine as disease-stabilizing treatment in acute myeloid leukemia

Background: A large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity. Previous studies have demonstrated that a subset of these patients can benefit from disease-stabilizing therapy based on all-trans retinoic acid (ATRA) and valproic acid. Even though complete hematological remission is only achieved for exceptional patients, a relatively large subset of patients respond to this treatment with stabilization of normal peripheral blood cell counts. Methods: In this clinical study we investigated the efficiency and safety of combining (i) continuous administration of valproic acid with (ii) intermittent oral ATRA treatment (21.5 mg/m2 twice daily) for 14 days and low-dose cytarabine (10 mg/m2 daily) for 10 days administered subcutaneously. If cytarabine could not control hyperleukocytosis it was replaced by hydroxyurea or 6-mercaptopurin to keep the peripheral blood blast count below 50 × 109/L. Results: The study included 36 AML patients (median age 77 years, range 48 to 90 years) unfit for conventional intensive chemotherapy; 11 patients responded to the treatment according to the myelodysplastic syndrome (MDS) response criteria and two of these responders achieved complete hematological remission. The most common response to treatment was increased and stabilized platelet counts. The responder patients had a median survival of 171 days (range 102 to > 574 days) and they could spend most of this time outside hospital, whereas the nonresponders had a median survival of 33 days (range 8 to 149 days). The valproic acid serum levels did not differ between responder and nonresponder patients and the treatment was associated with a decrease in the level of circulating regulatory T cells. Conclusion: Treatment with continuous valproic acid and intermittent ATRA plus low-dose cytarabine has a low frequency of side effects and complete hematological remission is seen for a small minority of patients. However, disease stabilization is seen for a subset of AML patients unfit for conventional intensive chemotherapy

Therapeutic use of valproic acid and all-trans retinoic acid in acute myeloid leukemia—literature review and discussion of possible use in relapse after allogeneic stem cell transplantation

Even though allogeneic stem cell transplantation is the most intensive treatment for acute myeloid leukemia (AML), chemo-resistant leukemia relapse is still one of the most common causes of death for these patients, as is transplant-related mortality, i.e., graft versus host disease, infections, and organ damage. These relapse patients are not always candidates for additional intensive therapy or re-transplantation, and many of them have decreased quality of life and shortened expected survival. The efficiency of azacitidine for treatment of posttransplant AML relapse has been documented in several clinical trials. Valproic acid is an antiepileptic fatty acid that exerts antileukemic activity through histone deacetylase inhibition. The combination of valproic acid and all-trans retinoic acid (ATRA) is well tolerated even by unfit or elderly AML patients, and low-toxicity chemotherapy (e.g., azacitidine) can be added to this combination. The triple combination of azacitidine, valproic acid, and ATRA may therefore represent a low-intensity and low-toxicity alternative for these patients. In the present review, we review and discuss the general experience with valproic acid/ATRA in AML therapy and we discuss its possible use in low-intensity/toxicity treatment of post-allotransplant AML relapse. Our discussion is further illustrated by four case reports where combined treatments with sequential azacitidine/hydroxyurea, valproic acid, and ATRA were used

A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation

Interleukin (IL)‐6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL‐6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL‐6 receptor has not been examined. We therefore investigated whether SNPs in the IL‐6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL‐6 promoter variant rs1800975 and the IL‐6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population‐based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL‐6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL‐6R levels; the decreased IL‐6R levels persisted 6 months post‐transplant. In contrast, patients being homozygous for the minor allele of the IL‐6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL‐6R rs4845618 donor genotype showed an association with severe acute graft‐versus‐host disease (GVHD), whereas the donor genotype of the IL‐6 SNP rs1800795 was associated with decreased survival 100 days post‐transplant. Finally, the recipient genotype of the IL‐6R SNP rs4329505 showed a strong association with 2‐years non‐relapse mortality, and this effect was also highly significant in multivariate analysis. IL‐6 and IL‐6R SNPs influence the clinical outcome after allogeneic stem cell transplantation

A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation

Interleukin (IL)‐6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL‐6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL‐6 receptor has not been examined. We therefore investigated whether SNPs in the IL‐6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL‐6 promoter variant rs1800975 and the IL‐6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population‐based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL‐6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL‐6R levels; the decreased IL‐6R levels persisted 6 months post‐transplant. In contrast, patients being homozygous for the minor allele of the IL‐6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL‐6R rs4845618 donor genotype showed an association with severe acute graft‐versus‐host disease (GVHD), whereas the donor genotype of the IL‐6 SNP rs1800795 was associated with decreased survival 100 days post‐transplant. Finally, the recipient genotype of the IL‐6R SNP rs4329505 showed a strong association with 2‐years non‐relapse mortality, and this effect was also highly significant in multivariate analysis. IL‐6 and IL‐6R SNPs influence the clinical outcome after allogeneic stem cell transplantation

Adult presentation of ornithine transcarbamylase deficiency: a possible cause of hyperammonemia after high-dose chemotherapy and stem cell transplantation

ABSTRACTHyperammonemia is a rare and often fatal complication following the conditioning therapy in autologous and allogeneic stem cell transplant recipients. It is characterized by anorexia, vomiting, lethargy and coma without any other apparent cause. The diagnosis is often delayed because symptoms can be subtle and ammonia is usually not included among the routine analyzes. Previous reports have not identified the molecular mechanisms behind hyperammonemia in stem cell transplant recipients. Urea cycle disorders (UCDs) are inborn errors of metabolism leading to hyperammonemia that usually presents in early childhood, whereas first presentation in adults is less common. Here we describe an adult woman with hyperammonemia following autologous stem cell transplantation for multiple myeloma. No apparent cause of hyperammonemia was identified, including portosystemic shunting, liver dysfunction or recent hyperammonemia-inducing chemotherapy. Hyperammonemia, normal blood glucose as well as anion gap and a previous history of two male newborns that died early after birth, prompted biochemical and genetic investigations for a UCD. A heterozygous variant in the X-linked gene encoding ornithine transcarbamylase (OTC) was identified and was regarded as a cause of UCD. The patient improved after treatment with nitrogen scavengers and high caloric intake according to a UCD protocol. This case report suggests that UCD should be considered as a possible cause of hyperammonemia following stem cell transplantation

Immunological Heterogeneity of Healthy Peripheral Blood Stem Cell Donors—Effects of Granulocyte Colony-Stimulating Factor on Inflammatory Responses

Interleukin-6 (IL-6) contributes to the development of immune-mediated complications after allogeneic stem cell transplantation. However, systemic IL-6 levels also increase during granulocyte colony-stimulating factor (G-CSF) mobilization of hematopoietic stem cells in healthy donors, but it is not known whether this mobilization alters systemic levels of other IL-6 family cytokines/receptors and whether such effects differ between donors. We examined how G-CSF administration influenced C-reactive protein (CRP) levels (85 donors) and serum levels of IL-6 family cytokines/receptors (20 donors). G-CSF increased CRP levels especially in elderly donors with high pretherapy levels, but these preharvesting levels did not influence clinical outcomes (nonrelapse mortality, graft versus host disease). The increased IL-6 levels during G-CSF therapy normalized within 24 h after treatment. G-CSF administration did not alter serum levels of other IL-6-familly mediators. Oncostatin M, but not IL-6, showed a significant correlation with CRP levels during G-CSF therapy. Clustering analysis of mediator levels during G-CSF administration identified two donor subsets mainly characterized by high oncostatin M and IL-6 levels, respectively. Finally, G-CSF could increase IL-6 release by in vitro cultured monocytes, fibroblasts, and mesenchymal stem cells. In summary, G-CSF seems to induce an acute phase reaction with increased systemic IL-6 levels in healthy stem cell donors

IL-6 Responsiveness of CD4+ and CD8+ T Cells after Allogeneic Stem Cell Transplantation Differs between Patients and Is Associated with Previous Acute Graft versus Host Disease and Pretransplant Antithymocyte Globulin Therapy

Graft-versus-host disease (GVHD), one of the most common and serious complications after allogeneic stem cell transplantation, is mediated by allocative T cells. IL-6 mediates both pro- and anti-inflammatory effects and modulates T cell response through classical signaling and trans-signaling. We investigated the effects on the mTOR and JAK/STAT pathways after various types of IL-6 signaling for circulating T cells were derived from 31 allotransplant recipients 90 days post-transplant. Cells were stimulated with IL-6 alone, hyper-IL-6 (trans-signaling), IL-6+IL-6 receptor (IL-6R; classical + trans-signaling) and IL-6+IL-6R+soluble gp130-Fc (classical signaling), and flow cytometry was used to investigate the effects on phosphorylation of AKT (Thr308), mTOR (Ser2442), STAT3 (Ser727) and STAT3 (Tyr705). CD3+CD4+ and CD3+C8+ T cells responded to classical and trans IL-6 stimulation with increased STAT3 (Tyr705) phosphorylation; these responses were generally stronger for CD3+CD4+ cells. STAT3 (Tyr705) responses were stronger for patients with previous acute GVHD; CD3+CD4+ cells from GVHD patients showed an additional STAT3 (Ser727) response, whereas patients without acute GVHD showed additional mTOR (Ser2448) responses. Furthermore, treatment with antithymocyte globulin as a part of GVHD prophylaxis was associated with generally weaker STAT3 (Tyr705) responses and altered STAT3 (Ser727) responsiveness of CD3+CD4+ cells together with increased mTOR (Ser2448) responses for the CD3+CD8+ cells. Thus, early post-transplant CD3+CD4+ and CD3+ CD8+ T cell subsets differ in their IL-6 responsiveness; this responsiveness is modulated by antithymocyte globulin and differs between patients with and without previous acute GVHD. These observations suggest that allotransplant recipients will be heterogeneous with regard to the effects of post-transplant IL-6 targeting.publishedVersio