scholarly journals Recent Progress in Interferon Therapy for Myeloid Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Fiona M. Healy ◽  
Lekh N. Dahal ◽  
Jack R.E. Jones ◽  
Yngvar Floisand ◽  
John F. Woolley
Keyword(s):  
Stem Cell ◽  
Myeloid Leukaemia ◽  
Haematopoietic Stem Cell ◽  
Polycythaemia Vera ◽  
Type I ◽  
Cell Transplant ◽  
Bone Marrow Niche ◽  
Term Survival ◽  
Myeloid Malignancies ◽  
The Impact

Myeloid malignancies are a heterogeneous group of clonal haematopoietic disorders, caused by abnormalities in haematopoietic stem cells (HSCs) and myeloid progenitor cells that originate in the bone marrow niche. Each of these disorders are unique and present their own challenges with regards to treatment. Acute myeloid leukaemia (AML) is considered the most aggressive myeloid malignancy, only potentially curable with intensive cytotoxic chemotherapy with or without allogeneic haematopoietic stem cell transplantation. In comparison, patients diagnosed with chronic myeloid leukaemia (CML) and treated with tyrosine kinase inhibitors (TKIs) have a high rate of long-term survival. However, drug resistance and relapse are major issues in both these diseases. A growing body of evidence suggests that Interferons (IFNs) may be a useful therapy for myeloid malignancies, particularly in circumstances where patients are resistant to existing front-line therapies and have risk of relapse following haematopoietic stem cell transplant. IFNs are a major class of cytokines which are known to play an integral role in the non-specific immune response. IFN therapy has potential as a combination therapy in AML patients to reduce the impact of minimal residual disease on relapse. Alongside this, IFNs can potentially sensitize leukaemic cells to TKIs in resistant CML patients. There is evidence also that IFNs have a therapeutic role in myeloproliferative neoplasms (MPNs) such as polycythaemia vera (PV) and primary myelofibrosis (PMF), where they can restore polyclonality in patients. Novel formulations have improved the clinical effectiveness of IFNs. Low dose pegylated IFN formulations improve pharmacokinetics and improve patient tolerance to therapies, thereby minimizing the risk of haematological toxicities. Herein, we will discuss recent developments and the current understanding of the molecular and clinical implications of Type I IFNs for the treatment of myeloid malignancies.

TGFB1 Functional Polymorphisms: Impact on Outcome in Allogeneic Unrelated Donor Haematopoietic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3011-3011
Author(s):  
Mariano Berro ◽  
Louise Cooke ◽  
Neema P Mayor ◽  
Gustavo Kusminsky ◽  
Steven G.E. Marsh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Myeloid Leukaemia ◽  
Cell Transplantation ◽  
Haematopoietic Stem Cell Transplantation ◽  
Haematopoietic Stem Cell ◽  
Wild Type ◽  
Functional Polymorphisms ◽  
The Impact ◽  
Donor Genotype

Abstract Allogeneic haematopoietic stem cell transplantation (HSCT) using volunteer unrelated donors (UD) is a life-saving intervention for patients with haematological malignancies. It is recognised that numerous genetic factors in both patient and donor play a role in outcome. TGF beta 1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes and may play a role in carcinogenesis. Several functional polymorphisms have been identified, such as a single nucleotide polymorphism (SNP) at codon 10 (c.29T>C, p.L10P) of exon 1. Conflicting data has been published regarding the impact of the SNP on plasma levels and its role in sibling HSCT. To date there are no published data in UD HSCT. We hypothesised that this polymorphism may influence the outcome of UD HSCT by modulating the immune response. We genotyped, for the presence of a SNP at codon 10, a large group of patient/donor pairs (314) who underwent an UD HSCT using a donor provided by the Anthony Nolan Trust, in a UK transplant centre. The transplant took place between 1997 and 2006 and the median follow up time was 5.8 years (0.8–10.18 years). The diagnoses were chronic myeloid leukaemia 69 (21%), acute lymphoid leukaemia 76 (24%), acute myeloid leukaemia 76 (24%), myelodysplasic syndrome 25 (8%), lymphoproliferatives disorders 37 (11.8%) and others 31 (9.9%). Myeloablative conditioning regimens were used in 69.9% of transplants; T-cell depletion was included in 86.9% of conditioning protocols. Sixty eight percent of the transplants were full matched (10/10), and 12.7% were 12/12. The patients’ observed SNP frequencies were TC 55.7%, TT 32% and CC 12.1%, and for the donor were 51%, 34.7% and 14.3% respectively. There were no significant effects of the presence of a SNP in either the patient or donor groups alone. However, when we analysed the impact of the total number of SNPs present in the pair, we found that multiple SNPs (3–4 SNPs vs 2 or less) were associated with a significantly decreased overall survival (OS) (5 years: 30% vs 42%, log-rank p=0.04), disease free survival (DFS) (5 years: 17% vs 25%, log-rank p=0.02) and a higher treatment related mortality (1 and 3 years: 42% and 45% vs 25% and 30%, respectively, log-rank p=0.03). In multivariate analysis there was a trend to improved OS in the pairs with fewer SNPs (HR: 0.7; 95% CI 0.4,1.0; p=0.07). We speculated that the impact of the donor genotype might differ depending on the patient genotype. In patients with a wild type genotype, the donor genotype did not impact significantly on outcome. Conversely, the patients with a SNP at codon 10 (TC or CC), had significantly better DFS when using a donor with a wild type genotype compared to those with a SNP present (5 years: 34% vs 21%; log-rank p= 0.04). In conclusion, we have shown for the first time in a large number of UD HSCT pairs that increased numbers of SNPs in the TGFB1 gene at codon 10 in patients and donors are associated with a worse outcome following UD HSCT. While an exact functional mechanism remains unclear, these data emphasise the importance of pursuing functional analyses of TGF beta in this setting. In addition, identification of these SNPs pre-transplant will allow for transplant conditioning and immunosuppression regimens to be tailored to the individual patient, as well as assisting in the most appropriate choice of donor.

scholarly journals NOD2 Polymorphisms and Their Impact on Haematopoietic Stem Cell Transplant Outcome

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Neema P. Mayor ◽  
Bronwen E. Shaw ◽  
J. Alejandro Madrigal ◽  
Steven G. E. Marsh
Keyword(s):  
Stem Cell ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Inflammatory Responses ◽  
Haematopoietic Stem Cell ◽  
Cell Transplant ◽  
Gene Markers ◽  
The Impact ◽  
Transplant Complications ◽  
Candidate Gene Markers

Haematopoietic stem cell transplantation (HSCT) is a valuable tool in the treatment of many haematological disorders. Advances in understanding HLA matching have improved prognoses. However, many recipients of well-matched HSCT develop posttransplant complications, and survival is far from absolute. The pursuit of novel genetic factors that may impact on HSCT outcome has resulted in the publication of many articles on a multitude of genes. Three NOD2 polymorphisms, identified as disease-associated variants in Crohn’s disease, have recently been suggested as important candidate gene markers in the outcome of HSCT. It was originally postulated that as the clinical manifestation of inflammatory responses characteristic of several post-transplant complications was of notable similarity to those seen in Crohn’s disease, it was possible that they shared a common cause. Since the publication of this first paper, numerous studies have attempted to replicate the results in different transplant settings. The data has varied considerably between studies, and as yet no consensus on the impact of NOD2 SNPs on HSCT outcome has been achieved. Here, we will review the existing literature, summarise current theories as to why the data differs, and suggest possible mechanisms by which the SNPs affect HSCT outcome.

Donor KIR Genotype Does Not Affect VZV Reactivation after Allogeneic Haematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3236-3236
Author(s):  
Sujaatha Narayanan ◽  
Sandeep Nagra ◽  
Premini Mahendra ◽  
Fiona J. Clark ◽  
Charles F. Craddock ◽  
...  
Keyword(s):  
At Risk ◽  
Stem Cell ◽  
Protective Effect ◽  
Haematopoietic Stem Cell ◽  
Cell Transplant ◽  
Allogeneic Hsct ◽  
Donor Type ◽  
The Individual ◽  
The Impact ◽  
Cmv Reactivation

Abstract Background. Varicella zoster virus (VZV) reactivation is a common occurrence after allogeneic haematopoietic stem cell transplant (HSCT) and a cause of significant morbidity. We have recently demonstrated the protective effect of donor KIR genotpye against cytomegalovirus (CMV) reactivation- specifically the protective effect of the broad ’B’ haplotype containing multiple activating KIR genes1. This retrospective study was designed to investigate whether donor KIR genotype confers an equivalent protective effect against VZV reactivation. Method. 152 patients who underwent allogeneic HSCT at a single centre were identified. Those with pre-transplant serology consistent with previous exposure to VZV were defined as at risk of VZV reactivation. All patients received aciclovir 800mg daily as routine prophylaxis. The diagnosis of VZV reactivation was made clinically. Cases of VZV reactivation were identified by examination of the case records. KIR genotyping was performed on donor DNA using PCR-SSP. The individual KIR genes KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5 and 3DS1, as well as the broad KIR haplotypes ’A’ and ’B’, were assessed by univariate and multivariate analysis for an effect on VZV reactivation. Also assessed was the impact of recipient HLA-C type, recipient HLA-Bw4/Bw6, donor type (sex-matched sibling, sex-mismatched sibling, volunteer unrelated), reduced intensity conditioning (RIC) regimen, the use of alemtuzemab as in vivo T cell depletion, CMV reactivation, and grade 2 or greater GVHD requiring steroid therapy. Results. 128 (84.2%) patients had evidence of past infection and thus were deemed at risk of VZV reactivation. Of these, 47 (36.7%) had clinical evidence of reactivation. 60% of transplants were from a donor possessing the broad ’B’ haplotype. The rate of reactivation in the presence of donor ’B’ haplotype was 40% compared to 32% when no donor ’B’ haplotype was present (p=0.237). None of the individual donor KIRs were shown to significantly reduce the rate of VZV reactivation. Neither the use of a RIC regimen nor the presence of alemtuzemab in the conditioning regimen were shown to have an impact. None of the other factors analysed were associated with an increased rate of zoster reactivation. Conclusion. Donor KIR genotype does not influence VZV reactivation after allogeneic HSCT. This contrasts with the findings for CMV reactivation. No influence of donor type, conditioning or GVHD could be demonstrated. This suggests 1) that there are differing mechanisms that control the reactivation of different Herpes viruses after transplantation and 2) that KIRs may have specificity for CMV.

Increased MSI2 expression Is Associated with Aggressive CML and AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2516-2516
Author(s):  
Jaspal S Kaeda ◽  
Ken I. Mills ◽  
Michael G Kharas ◽  
Giuseppe Saglio ◽  
Michaela Schwarz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Myeloid Leukaemia ◽  
Median Survival ◽  
Normal Control ◽  
Advanced Disease ◽  
Haematopoietic Stem Cell ◽  
Cell Transplant ◽  
Control Gene ◽  
Expression Levels

Abstract Abstract 2516 The events triggering arrested differentiation and a more aggressive disease in chronic myeloid leukaemia (CML) patients are unclear. Dysregulation of MSI2 has been suggested as a causal event in the transformation of chronic phase (CP), a relatively indolent disease phase, to blast crisis (BC), which is usually fatal. The Musashi gene family, regulated by HOXA9, has been shown to control critical cell fate decisions by binding to the 3'untranslated region of target mRNAs, thereby inhibiting translation. This results in dysfunction of the regulatory pathway, leading to hematopoietic stem cell (HSC) proliferation, impaired myeloid differentiation and worse clinical prognosis in CML and AML. In this study we attempt to verify these published results and test the utility of using MSI2 as a prognostic marker in CML and AML. To assess if MSI2 expression levels might be prognostic in CML, we screened 65 heterogeneous patients [median age; 45 years (19–75); M:35; F:30] of whom 54 were in CP and 11 in advanced disease, treated with different modalities. Of these 64 were administered one or more of the tyrosine kinase inhibitors, of these 2 underwent haematopoietic stem cell transplant. One patient was managed with interferon plus cytarabine only. BCR-ABL1 Kinase domain mutations were documented in 8 of the 11 patients in advanced disease, of which 3 were T315I in combination with another mutation and 4 mapped to the P-loop. Of the 30 CP patients screened 10 had KD mutation, of which one was T315I and 2 were within the P-loop. The overall median survival for 11 patients in advanced disease [2 accelerated phase; 9 BC (4 myeloid, 5 lymphoid)] is 3.9 years (1.1–19.0), 7 of the BC had died (median survival 4.0 years). All the CP patients are alive with an overall median survival of 3.54 years (0.46–16.4). In addition we screened 89 diagnostic samples from acute myeloid leukaemia (AML) patients (M:53; F:36) with a median age of 61 years (8–85) and 27 normal control blood donor samples. The MSI2, BCR-ABL1 and GUSß endogenous control gene) mRNA expression were measured by TaqMan real time quantitative polymerase chain reaction (RQ-PCR) in separate assays. The MSI2 and GUSß mRNA were measured in duplicate and BCR-ABL1 in triplicate as were the standards for the three genes assayed. The data were expressed as % ratio of the control gene, only samples with >5500 GUSß copies were included in the data presented here. Msi2 expression was detected in all samples by RQ-PCR but was significantly increased (p=<0.0001) in advanced disease CML patients [median 6.7 (1.3–22.9)], irrespective of lymphoid or myeloid transformation, when compared with CML CP subjects [median 2.2 (0.2–6.3)]. BCR-ABL1 was detectable in all CML samples. The median for BCR-ABL1 copies in the 11 advanced disease patients was 101.4 (0.3–325.8). Remarkably, when patients in CP were classified as less and greater than the 2.16 MSI2 median, the BCR-ABL1 mRNA median values were 19.4 (0.1–1000) and 1.31 (0.02–393) transcripts, respectively, i.e. higher MSI2 expression was associated with lower BCR-ABL1 transcripts (p=0.023). Furthermore, there was no significant difference in MSI2 expression between the normal control population [median 2.16 (1.33–7.53)] and CP patients (p=0.204). The 89 AML samples had a median MSI2 value of 3.67 (0.41–40.17). Outcome data was available for 86 and these were classified into tertiles (low, intermediate and high MSI2). Kaplan-Meier survival analysis revealed a p value of 0.088 when comparing the outcome of patients in the low and high groups and 0.091 between low and intermediate/high. Although this is a small cohort, the difference in outcome was due to only 4 out of 26 (15.4%) patients in the low group who had died with a mean survival of 525 days (182–840); compared to 17 out of 53 (32%) in the intermediate/High group with a mean survival of 52 days (1–120). In summary, our data identified an inverse relationship between MSI2 and BCR-ABL1 expression levels in CP patients. These observations may reflect the finding of lower expression of HOXA family and MSI2 in quiescent CML stem cells compared to normal stem cells. A longitudinal study among the CP patients might indicate how it effects their overall survival. We also provide evidence that increased MSI2 expression correlates with an aggressiveness of CML and early death in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Assessing the impact on intestinal microbiome and clinical outcomes of antibiotherapy optimisation strategies in haematopoietic stem cell transplant recipients: study protocol for the prospective multicentre OptimBioma study

BMJ Open ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. e034570
Author(s):  
Silvia Jiménez-Jorge ◽  
Gema Labrador-Herrera ◽  
Clara M Rosso-Fernández ◽  
Nancy Rodríguez-Torres ◽  
María Eugenia Pachón-Ibáñez ◽  
...  
Keyword(s):  
Stem Cell ◽  
Clinical Outcomes ◽  
Intestinal Microbiota ◽  
Acute Gvhd ◽  
Haematopoietic Stem Cell ◽  
Cell Transplant ◽  
Microbiota Composition ◽  
Prospective Longitudinal ◽  
The Impact ◽  
Microbiota Diversity

IntroductionHaematopoietic stem cell transplantation (HSCT) is a life-saving treatment for a number of haematological diseases. Graft versus host disease (GVHD) is its main complication and hampers survival. There is strong evidence that intestinal microbiota diversity of the recipient may increase the risk of GVHD worsening survival. Antibiotic regimens used during the early phase of the transplant may influence clinical outcomes by reducing intestinal microbiota diversity. Present guidelines of European Conference on Infections in Leukaemia exhort to optimising antibiotic use in haematological patients including HSCT recipients. The present study aims to investigate if, in HSCT recipients, the optimisation of antibacterial use may preserve intestinal microbiota composition reducing the incidence and severity of acute GVHD and improving relevant clinical outcomes.Methods and analysisThis is a prospective longitudinal observational study of two cohorts of HSCT recipients: (1) the intervention cohort includes patients treated in centres in which a predefined strategy of antibiotherapy optimisation is implemented, with the objective of optimising and reducing antibiotic administration according to clinical criteria and (2) the control cohort includes patients treated in centres in which a classic permissive strategy of antibiotic prophylaxis and treatment is used. Adult patient receiving a first HSCT as a treatment for any haematological condition are included. Clinical variables are prospectively recorded and up to five faecal samples are collected for microbiota characterisation at prestablished peritransplant time points. Patients are followed since the preconditioning phase throughout 1-year post-transplant and four follow-up visits are scheduled. Faecal microbiota composition and diversity will be compared between both cohorts along with acute GVHD incidence and severity, severe infections rate, mortality and overall and disease-free survival.Ethics and disseminationThe study was approved between 2017 and 2018 by the Ethical Committees of participant centres. Study results will be disseminated through peer-reviewed journals and national and international scientific conferences.Trial registration numberNCT03727113

scholarly journals Late Effects After Haematopoietic Stem Cell Transplantation in ALL, Long-Term Follow-Up and Transition: A Step Into Adult Life

2021 ◽  
Vol 9 ◽  
Author(s):  
Tamara Diesch-Furlanetto ◽  
Melissa Gabriel ◽  
Olga Zajac-Spychala ◽  
Alessandro Cattoni ◽  
Bianca A. W. Hoeben ◽  
...  
Keyword(s):  
Stem Cell ◽  
Late Effects ◽  
Adult Life ◽  
Haematopoietic Stem Cell ◽  
Childhood And Adolescence ◽  
Cell Transplant ◽  
Adult Services ◽  
Timely Access ◽  
The Impact

Haematopoietic stem cell transplant (HSCT) can be a curative treatment for children and adolescents with very-high-risk acute lymphoblastic leukaemia (ALL). Improvements in supportive care and transplant techniques have led to increasing numbers of long-term survivors worldwide. However, conditioning regimens as well as transplant-related complications are associated with severe sequelae, impacting patients' quality of life. It is widely recognised that paediatric HSCT survivors must have timely access to life-long care and surveillance in order to prevent, ameliorate and manage all possible adverse late effects of HSCT. This is fundamentally important because it can both prevent ill health and optimise the quality and experience of survival following HSCT. Furthermore, it reduces the impact of preventable chronic illness on already under-resourced health services. In addition to late effects, survivors of paediatric ALL also have to deal with unique challenges associated with transition to adult services. In this review, we: (1) provide an overview of the potential late effects following HSCT for ALL in childhood and adolescence; (2) focus on the unique challenges of transition from paediatric care to adult services; and (3) provide a framework for long-term surveillance and medical care for survivors of paediatric ALL who have undergone HSCT.

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