Chronic GVHD Could Ameliorate the Impact of Adverse Somatic Mutations in Patients with Myelodysplastic Syndromes and Hematopoietic Stem Cell Transplantation

Purpose The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. Patients and Methods We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT. Results Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%. Conclusion Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.

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Impact of Activating Killer Immunoglobulin-Receptor Genotype of the Donor on Outcome of Unrelated Donor - Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v106.11.5206.5206 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5206-5206

Author(s):

Sebastian Giebel ◽

Izabela Nowak ◽

Tomasz Kruzel ◽

Jerzy Wojnar ◽

Miroslaw Markiewicz ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Nk Cells ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

The Impact

Abstract Function of NK cells is regulated by a balance between inhibitory and activating signals transmitted through killer immunoglobulin-like receptors (KIR). The goal of the present analysis was to evaluate the impact of donor activating KIR genotype (KIR2DS1 and KIR2DS2 loci) on outcome of unrelated donor-hematopoietic stem cell transplantation (URD-HSCT). Fourty-two URD-HSCT recipients with haematological malignancies, aged 28 (14–48) years (male/female - 26/16) were included in the analysis. The conditioning regimen was myeloablative and based on chemotherapy alone (n=33) or total body irradiation (n=9). Graft-vs-host disease (GVHD) prophylaxis consisted of cyclosporin, methotrexate, and pre-transplant anti-thymocyte globulin. Patients were grouped according to their donors’ activating KIR genotype including two loci: KIR2DS1 and KIR2DS2. The overall survival at 2.5 years with respect of the donors’ activating KIR genotype was as follows: KIR2DS1(−)DS2(−) (n=15) − 82% (+/−12%), KIR2DS1(+)DS2(−) (n=9) − 78% (+/−14%), KIR2DS1(−)DS2(+)− (n=7) 86% (+/−13%), KIR2DS1(+)DS2(+) (n=11) − 0%. The OS rate differed significantly between KIR2DS1(+)DS2(+) group and the remaining patients: 0% vs. 82% (+/−7%), p=0.03. The difference resulted mainly from higher cumulative incidence of non-relapse mortality in the KIR2DS1(+)DS2(+) group: 100% vs. 18% (+/−8%), p=0.098. The reasons of death in patients with KIR2DS1(+)DS2(+) donors were chronic GVHD (n=4) and acute GVHD (n=1). We conclude that the concomitance of both KIR2DS1 and KIR2DS2 in the donor is associated with high risk of mortality following URD-HSCT, resulting mainly from the incidence of severe GVHD. Whether this effect is associated with the activity of NK cells or KIR-bearing T lymphocytes requires further investigation.

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Chronic graft-versus-host disease could ameliorate the impact of adverse somatic mutations in patients with myelodysplastic syndromes and hematopoietic stem cell transplantation

Annals of Hematology ◽

10.1007/s00277-019-03751-6 ◽

2019 ◽

Vol 98 (9) ◽

pp. 2151-2162

Author(s):

Juan Carlos Caballero ◽

Mercedes Sánchez Barba ◽

Jesús María Hernández Sánchez ◽

Esperanza Such ◽

Kamila Janusz ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Myelodysplastic Syndromes ◽

Somatic Mutations ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

The Impact

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The Impact of Antithymocyte Globulin (ATG) Dose in Allogeneic Hematopoietic Stem Cell Transplantation with HLA Mismatched Donors

Blood ◽

10.1182/blood.v128.22.3393.3393 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3393-3393

Author(s):

Yunsuk Choi ◽

Ho Sup Lee ◽

Je-Hwan Lee ◽

Joon Ho Moon ◽

Ho-Jin Shin ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Antithymocyte Globulin ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Significant Difference ◽

The Impact

Abstract Background: Antithymocyte globulin (ATG) is usually included in conditioning regimens in hematopoietic stem cell transplantation (HSCT) from HLA mismatched donors to reduce the incidence of graft versus host disease (GVHD) and rejection. In this study, we intended to assess the clinical impact of ATG dose in HSCT from HLA mismatched donors. Patients and Methods: We retrospectively analyzed 268 consecutive patients with acute myeloid leukemia (n=159), acute lymphoblastic leukemia (n=49) or myelodysplastic syndrome (n=60) receiving busulfan based conditioning and HSCT with HLA mismatched sibling, unrelated, or haplo-identical family donors in five centers of Korea between 2005 and 2015. Results: The median age was 44.5 (range, 15-75) years. Fourty-two patients were treated with myeloablative conditioning and 226 patients with reduced intensity conditioning regimen. ATG at a total dose of 0 (n=31), 2.5-7.5 mg/kg (n = 16), 9 mg/kg (n = 164) or 12mg/kg (n=57) was given to patients according to protocol. 140 patients received HSCT in complete remission and 73 patients in relapse or refractory status. The median follow up duration for surviving patients was 33.8 (range, 2.0-100.6) months. The 3-year overall survival (OS) and event free survival (EFS) rate for all patients was 44.7% and 39.2% There was no significant difference of OS according to ATG dose (P=0.153), but ATG dose of 2.5-7.5mg/kg was significantly associated with better EFS than 0, 9 mg/kg, or 12mg/kg of ATG groups (79.1% vs. 45.4%, 38.9%, and 31.7%, respectively, P=0.038) (Table 1). In addition, ATG dose significantly affected on relapse (P=0.046). The relapse incidence in patients receiving 2.5-7.5 mg/kg of ATG was lower compared to those given 0, 9, or 12 mg/kg of ATG (6.7% for 2.5-7.5mg/kg of ATG group vs. 29.5%, 34.0%, and 46.9% for 0, 9, and 12 m/kg of ATG groups, respectively). The incidences of acute GVHD grades II-IV were 32.6%, 25.0%, 29.4% and 24.6% in patients receiving 0. 2.5-7.5, 9, and 12 mg/kg of ATG, respectively. The incidence of extensive chronic GVHD tended to be lower according to the increase of ATG dose (36.8%, 34.5%, 27.4%, and 21.1% for 0. 2.5-7.5, 9, and 12 mg/kg of ATG dose, respectively).In multivariate analysis, ATG dose of 9 mg/kg (P=0.023) and 12 mg/kg (P=0.036) was associated with shorter EFS compared to 2.5-7.5 mg/kg of ATG. Conclusion: 9mg/kg of ATG dose or more in HLA mismatched busulfan based HSCT with HLA mismatch donors increased the risk for relapse and reduced the EFS. Disclosures No relevant conflicts of interest to declare.

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The Impact of Allogeneic Hematopoietic Stem Cell Transplantation on Kidney Function in Children—A Single Center Experience

Journal of Clinical Medicine ◽

10.3390/jcm10051113 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1113

Author(s):

Kinga Musiał ◽

Krzysztof Kałwak ◽

Danuta Zwolińska

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Serum Creatinine ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Kidney Function ◽

Hematopoietic Stem ◽

Oncological Patients ◽

The Impact

Background: Knowledge about the impact of allogeneic hematopoietic stem cell transplantation (alloHSCT) on renal function in children is still limited. Objectives: The aim of the study was to evaluate kidney function in children undergoing alloHSCT, with special focus on differences between patients transplanted due to oncological and non-oncological indications. Materials and Methods: The data of 135 children undergoing alloHSCT were analyzed retrospectively. The serum creatinine and estimated glomerular filtration rate (eGFR) values were estimated before transplantation at 24 h; 1, 2, 3, 4 and 8 weeks; and 3 and 6 months after alloHSCT. Then, acute kidney injury (AKI) incidence was assessed. Results: Oncological children presented with higher eGFR values and more frequent hyperfiltration rates than non-oncological children before alloHSCT and until the 4th week after transplantation. The eGFR levels rose significantly after alloHSCT, returned to pre-transplant records after 2–3 weeks, and decreased gradually until the 6th month. AKI incidence was comparable in oncological and non-oncological patients. Conclusions: Children undergoing alloHSCT due to oncological and non-oncological reasons demonstrate the same risk of AKI, but oncological patients may be more prone to sustained renal injury. Serum creatinine and eGFR seem to be insufficient tools to assess kidney function in the early post-alloHSCT period, when hyperfiltration prevails, yet they reveal significant differences in long-term observation.

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The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy

Blood ◽

10.1182/blood-2003-10-3616 ◽

2004 ◽

Vol 103 (6) ◽

pp. 2003-2008 ◽

Cited By ~ 259

Author(s):

Michael Boeckh ◽

W. Garrett Nichols

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cohort Studies ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Preemptive Therapy ◽

Prevention Strategies ◽

Hematopoietic Stem ◽

The Impact

AbstractIn the current era of effective prophylactic and preemptive therapy, cytomegalovirus (CMV) is now a rare cause of early mortality after hematopoietic stem cell transplantation (HSCT). However, the ultimate goal of completely eliminating the impact of CMV on survival remains elusive. Although the direct effects of CMV (ie, CMV pneumonia) have been largely eliminated, several recent cohort studies show that CMV-seropositive transplant recipients and seronegative recipients of a positive graft appear to have a persistent mortality disadvantage when compared with seronegative recipients with a seronegative donor. Recipients of T-cell–depleted allografts and/or transplants from unrelated or HLA-mismatched donors seem to be predominantly affected. Reasons likely include both incomplete prevention of direct and indirect or immunomodulatory effects of CMV as well as consequences of drug toxicities. The effect of donor CMV serostatus on outcome remains controversial. Large multicenter cohort studies are needed to better define the subgroups of seropositive patients that may benefit from intensified prevention strategies and to define the impact of CMV donor serostatus in the era of high-resolution HLA matching. Prevention strategies may require targeting both the direct and indirect effects of CMV infection by immunologic or antiviral drug strategies.

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Review of Stem-Cell Transplantation for Myelodysplastic Syndromes in Older Patients in the Context of the Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome Emanating From the Centers for Medicare and Medicaid Services

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.1919 ◽

2011 ◽

Vol 29 (5) ◽

pp. 566-572 ◽

Cited By ~ 18

Author(s):

Sergio A. Giralt ◽

Mary Horowitz ◽

Daniel Weisdorf ◽

Corey Cutler

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Myelodysplastic Syndrome ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Myelodysplastic Syndromes ◽

Older Patients ◽

The United States ◽

Hematopoietic Stem

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem-cell disorders that result in varying degrees of cytopenia and risk of transformation into acute leukemia. Allogeneic stem-cell transplantation (SCT) is the only known cure for this disease. The treatment is routinely used for younger patients, but only a minority of patients older than the age of 60 undergo this procedure. The overall MDS incidence is 3.3 per 100,000, but the incidence in patients older than age 70 is between 15 and 50 per 100,000. The median age at presentation is 76 years. Medicare-age patients 65 or older represent 80% of the total population receiving an MDS diagnosis. In the United States, one of the obstacles to SCT for older patients with MDS has been lack of third party reimbursement. On August 4, 2010, the Centers for Medicare and Medicaid Services released their Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndrome. This memo states: “Allogeneic HSCT for MDS is covered by Medicare only for beneficiaries with MDS participating in an approved clinical study that meets the criteria below…. ” In this review, we will summarize what is known regarding the role of allogeneic SCT in older patients as well as other elements that should be included within clinical trials that can provide the evidence necessary to demonstrate that allogeneic SCT should be a covered benefit for Medicare beneficiaries.

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