ResearchPad - hematopoietic-stem-cell-transplantation https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Safety of tunneled central venous catheters in pediatric hematopoietic stem cell recipients with severe primary immunodeficiency diseases]]> https://www.researchpad.co/article/elastic_article_14693 Tunneled central venous catheters (TCVCs) provide prolonged intravenous access for pediatric patients with severe primary immunodeficiency disease (PID) undergoing hematopoietic stem cell transplantation (HSCT). However, little is known about the epidemiology and clinical significance of TCVC-related morbidity in this particular patient group. We conducted the retrospective analysis of patients with severe PID who received percutaneous landmark-guided TCVC implantation prior to HSCT. We analyzed 92 consecutive TCVC implantations in 69 patients (median [interquartile range] age 3.0 [0–11] years) with severe combined immune deficiency (n = 39, 42.4%), chronic granulomatous disease (n = 17, 18.4%), and other rare PID syndromes (n = 36, 39.2%). The median length of TCVC observation was 144.1 (85.5–194.6) days with a total of 14,040 catheter days at risk (cdr). The overall rate of adverse events during catheter insertion was 17.4% (n = 16) and 25.0% during catheter dwell period (n = 23, catheter risk [CR] per 1000 cdr = 1.64). The most common complication was TCVC-related infection with an overall prevalence of 9.8% (n = 9, CR = 0.64), followed by late dislocation (n = 6, 6.5%, CR = 0.43), early dislocation (n = 4, 4.3%) and catheter dysfunction (n = 4, 4.3%, CR = 0.28). TCVCs are safe in children with severe PID undergoing HSCT with relatively low rates of TCVC-related infection.

]]>
<![CDATA[Effect of Prophylactic Low Level Laser Therapy on Oral Mucositis: A Systematic Review and Meta-Analysis]]> https://www.researchpad.co/article/5989da36ab0ee8fa60b8640c

Background

Objective was to determine whether prophylactic low level laser therapy (LLLT) reduces the risk of severe mucositis as compared to placebo or no therapy.

Methods

MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched until February 2014 for randomized controlled trials (RCTs) comparing prophylactic LLLT with placebo or no therapy in patients with cancer or undergoing hematopoietic stem cell transplantation (HSCT). All analyses used random effects models.

Results

Eighteen RCTs (1144 patients) were included. Prophylactic LLLT reduced the overall risk of severe mucositis (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.20 to 0.67; P = 0.001). LLLT also reduced the following outcomes when compared to placebo/no therapy: severe mucositis at the time of anticipated maximal mucositis (RR 0.34, 95% CI 0.20 to 0.59), overall mean grade of mucositis (standardized mean difference −1.49, 95% CI −2.02 to −0.95), duration of severe mucositis (weighted mean difference −5.32, 95% CI −9.45 to −1.19) and incidence of severe pain (RR 0.26, 95% CI 0.18 to 0.37).

Conclusion

Prophylactic LLLT reduced severe mucositis and pain in patients with cancer and HSCT recipients. Future research should identify the optimal characteristics of LLLT and determine feasibility in the clinical setting.

]]>
<![CDATA[Impact of Donor Activating KIR Genes on HSCT Outcome in C1-Ligand Negative Myeloid Disease Patients Transplanted with Unrelated Donors—A Retrospective Study]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdcd34

Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14–1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05–1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01–1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01–1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15–1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91–1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01–1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90–1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01–1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90–1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08–0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11–0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13–0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26–5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance.

]]>
<![CDATA[The demanding attention of tuberculosis in allogeneic hematopoietic stem cell transplantation recipients: High incidence compared with general population]]> https://www.researchpad.co/article/5989db51ab0ee8fa60bdc4b1

Background

The risk of developing tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is expected to be relatively high in an intermediate TB burden country. This single-center retrospective study was conducted to investigate risk factors and the incidence of TB after allogeneic HSCT.

Methods

From January 2004 to March 2011, 845 adult patients were enrolled. Starting April 2009, patients were given isoniazid (INH) prophylaxis based on interferon-γ release assay results. The incidence of TB was analyzed before and after April 2009, and compared it with that of the general population in Korea.

Results

TB was diagnosed in 21 (2.49%) of the 845 allogeneic HSCT patients. The median time to the development of TB was 386 days after transplantation (range, 49–886). Compared with the general population, the standardized incidence ratio of TB was 9.10 (95% CI; 5.59–14.79). Extensive chronic graft-versus-host disease (GVHD) was associated with the development of TB (P = 0.003). Acute GVHD, conditioning regimen with total body irradiation and conditioning intensity were not significantly related. INH prophylaxis did not reduce the incidence of TB (P = 0.548). Among 21 TB patients, one patient had INH prophylaxis.

Conclusion

Allogeneic HSCT recipients especially those who suffer from extensive chronic GVHD are at a high risk of developing TB. INH prophylaxis did not statistically change the incidence of TB, however, further well-designed prospective studies are needed.

]]>
<![CDATA[Long-Term Stable Mixed Chimerism after Hematopoietic Stem Cell Transplantation in Patients with Non-Malignant Disease, Shall We Be Tolerant?]]> https://www.researchpad.co/article/5989daf3ab0ee8fa60bc21e1

Long-term stable mixed chimerism is a rare and poorly understood phenomenon post hematopoietic stem cell transplantation. This study aims to shed light on whether the two hematopoietic systems in patients with mixed chimerism remain functional. Additionally, we investigate possible immunologic differences in these individuals compared to patients with only donor derived immune cells. Patients with donor and mixed chimerism, at median 10 (5–16) years post-HSCT for non-malignant diseases, were assessed regarding clinical situation and immune system (phenotypical and functional). No difference in long-term outcome was seen in terms of general wellbeing, central phenotypic immune system features (e.g., differentiation status, CD4/CD8 ratio, B and NK-cell frequency) and antibody responses to immunizations. At a median of 10 years post transplantation, patients with mixed chimerism had significantly higher IgG3 and platelet levels. Additionally, these patients had higher NKT-cell levels (CD94+CD8+ and CD56+CD8+) than patients with donor chimerism. In depth phenotypic analysis of patients with mixed chimerism demonstrated recipient-derived fractions in most immune cell lineages (e.g., T-cell, B-cell and NK-cell subsets). Recipient cells were also capable of responding to mitogenic stimulation with production of several cytokines. In conclusion, long-term mixed chimerism did not negatively affect patient wellbeing and long-term outcome. Moreover, recipient-derived immunity may still be functional in these patients, suggesting an active state of tolerance and immunologic dependence on both hematopoietic systems.

]]>
<![CDATA[Minimal Residual Disease at First Achievement of Complete Remission Predicts Outcome in Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia]]> https://www.researchpad.co/article/5989daf0ab0ee8fa60bc1192

We evaluated the prognostic effect of minimal residual disease at first achievement of complete remission (MRD at CR1) in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL). A total of 97 patients received treatment in our center between 2007 and 2012 were retrospectively reviewed in this study. Patients were divided into two arms according to the post-remission therapy (chemotherapy alone or allogeneic hematopoietic stem cell transplantation (allo-HSCT)) they received. MRD was detected by four-color flow cytometry. We chose 0.02% and 0.2% as the cut-off points of MRD at CR1 for risk stratification using receiver operating characteristic analysis. The 3-year overall survival (OS) and leukemia free survival (LFS) rates for the whole cohort were 46.2% and 40.5%. MRD at CR1 had a significantly negative correlation with survival in both arms. Three-year OS rates in the chemotherapy arm were 70.0%, 25.2%, 0% (P = 0.003) for low, intermediate, and high levels of MRD at CR1, respectively. Three-year OS rates in the transplant arm were 81.8%, 64.3%, 27.3% (P = 0.005) for low, intermediate, and high levels of MRD at CR1, respectively. Multivariate analysis confirmed that higher level of MRD at CR1 was a significant adverse factor for OS and LFS. Compared with chemotherapy alone, allo-HSCT significantly improved LFS rates in patients with intermediate (P = 0.005) and high (P = 0.022) levels of MRD at CR1, but not patients with low level of MRD at CR1 (P = 0.851). These results suggested that MRD at CR1 could strongly predict the outcome of adult ALL. Patients with intermediate and high levels of MRD at CR1 would benefit from allo-HSCT.

]]>
<![CDATA[Improvement of the Outcome of Relapsed or Refractory Acute Lymphoblastic Leukemia in Children Using a Risk-Based Treatment Strategy]]> https://www.researchpad.co/article/5989d9dbab0ee8fa60b678a1

Relapsed/refractory acute lymphoblastic leukemia (ALL) is a leading cause of death by cancer in children. Our institution has switched relapse treatment strategy to improve survival. We reviewed records of first relapse/refractory childhood ALL between 1996 and 2012. Based on length of first remission, relapse site and immunophenotype, patients were classified into two groups: standard-risk relapse (SRR) and high-risk relapse and refractory (HRRR). Before 2007, all patients were uniformly treated with the same induction as at presentation, followed by hematopoietic stem cell transplantation (HSCT). Since 2007, treatment was given according to risk of failure: SRR were mostly treated with chemotherapy; HRRR patients underwent HSCT after intensive chemotherapy, aiming reduction of pre-transplant disease burden. Sixty-four patients were included. Thirty (47%) were SRR and 34 (53%) HRRR, including 11 with refractory ALL. Five-years overall survival (OS) and event-free survival (EFS) were similar for SRR, but were significantly higher with new risk-based strategy for HRRR: 56% versus 17% (P = 0.03) for OS, and 56% vs 11% for EFS (P = 0.008), respectively. In multivariate analysis, treatment strategy was significantly associated with survival. In conclusion, change for a risk-based strategy in our institution increased survival of high-risk patients to levels similar of those of standard-risk patients.

]]>
<![CDATA[Prognostic Impact of IPSS-R and Chromosomal Translocations in 751 Korean Patients with Primary Myelodysplastic Syndrome]]> https://www.researchpad.co/article/5989dac3ab0ee8fa60bb1730

Chromosomal translocations are rare in myelodysplastic syndrome (MDS) and their impact on overall survival (OS) and response to hypomethylating agents (HMA) is unknown. The prognostic impact of the revised International Prognostic Scoring System (IPSS-R) and for chromosomal translocations was assessed in 751 patients from the Korea MDS Registry. IPSS-R effectively discriminated patients according to leukaemia evolution risk and OS. We identified 40 patients (5.3%) carrying translocations, 30 (75%) of whom also fulfilled complex karyotype criteria. Translocation presence was associated with a shorter OS (median, 12.0 versus 79.7 months, P < 0.01). Multivariate analysis demonstrated that translocations (hazard ratio [HR] 1.64 [1.06–2.63]; P = 0.03) as well as age, sex, IPSS-R, and CK were independent predictors of OS. In the IPSS-R high and very high risk subgroup (n = 260), translocations remained independently associated with OS (HR 1.68 [1.06–2.69], P = 0.03) whereas HMA treatment was not associated with improved survival (median OS, 20.9 versus 21.2 months, P = 0.43). However, translocation carriers exhibited enhanced survival following HMA treatment (median 2.1 versus 12.4 months, P = 0.03). Our data suggest that chromosomal translocation is an independent predictor of adverse outcome and has an additional prognostic value in discriminating patients with MDS having higher risk IPSS-R who could benefit from HMA treatment.

]]>
<![CDATA[Prediction of Hematopoietic Stem Cell Transplantation Related Mortality- Lessons Learned from the In-Silico Approach: A European Society for Blood and Marrow Transplantation Acute Leukemia Working Party Data Mining Study]]> https://www.researchpad.co/article/5989dac6ab0ee8fa60bb2735

Models for prediction of allogeneic hematopoietic stem transplantation (HSCT) related mortality partially account for transplant risk. Improving predictive accuracy requires understating of prediction limiting factors, such as the statistical methodology used, number and quality of features collected, or simply the population size. Using an in-silico approach (i.e., iterative computerized simulations), based on machine learning (ML) algorithms, we set out to analyze these factors. A cohort of 25,923 adult acute leukemia patients from the European Society for Blood and Marrow Transplantation (EBMT) registry was analyzed. Predictive objective was non-relapse mortality (NRM) 100 days following HSCT. Thousands of prediction models were developed under varying conditions: increasing sample size, specific subpopulations and an increasing number of variables, which were selected and ranked by separate feature selection algorithms. Depending on the algorithm, predictive performance plateaued on a population size of 6,611–8,814 patients, reaching a maximal area under the receiver operator characteristic curve (AUC) of 0.67. AUCs’ of models developed on specific subpopulation ranged from 0.59 to 0.67 for patients in second complete remission and receiving reduced intensity conditioning, respectively. Only 3–5 variables were necessary to achieve near maximal AUCs. The top 3 ranking variables, shared by all algorithms were disease stage, donor type, and conditioning regimen. Our findings empirically demonstrate that with regards to NRM prediction, few variables “carry the weight” and that traditional HSCT data has been “worn out”. “Breaking through” the predictive boundaries will likely require additional types of inputs.

]]>
<![CDATA[The Impact of Methylenetetrahydrofolate Reductase C677T Polymorphism on Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Methotrexate Prophylaxis]]> https://www.researchpad.co/article/5989dae9ab0ee8fa60bbe65a

Pharmacogenomics can explain the inter-individual differences in response to drugs, including methotrexate (MTX) used for acute graft-versus-host disease (aGVHD) prophylaxis during hematopoietic stem cell transplantation (HSCT). In real-world practice, preplanned MTX dose is arbitrarily modified according to observed toxicity which can lead to unexpected and severe aGVHD development. We aimed to validate the influence of MTHFR C677T polymorphism on the outcomes of allogenic HSCT in a relatively under-represented homogenous Asian population. A total of 177 patients were divided into 677TT group versus 677C-carriers (677CT+677CC), and clinical outcomes along with baseline characteristics were analyzed and compared. Although there was a tendency towards increased peak liver function test results and accordingly greater delta values between the highest and the baseline in 677TT group, we found no associations between genotypes and hepatotoxicity. However, the incidence of acute liver GVHD (≥ grade 2) was significantly higher in the 677TT group than in the 677CC + 677CT group (P = 0.016). A total of 25 patients (14.1%) expired due to transplantation related mortality (TRM) during the first 180 days after HSCT. Patients carrying 677TT genotype were more likely to experience early TRM than 677C-carriers. The same pattern was observed in the cumulative TRM rate, and 677TT genotype patients were more prone to cumulative TRM (P = 0.010). This translated into shorter OS for patients with 677TT compared to 677C-carriers (P = 0.010). The 3-year survival after HSCT was 29.9% for 677TT cases and 47.1% for 677C-carriers. The multivariate analysis identified 677TT genotype (HR = 1.775. 95% CI 1.122–2.808, P = 0.014) and non-CR state (HR = 2.841. 95% CI 1.627–4.960, P<0.001) as predictors for survival. In conclusion, the MTHFR 677TT genotype appears to be associated with acute liver GVHD, and represent a risk factor for TRM and survival in patients undergoing HSCT with MTX as GVHD prophylaxis.

]]>
<![CDATA[Topical Recombinant Human Epidermal Growth Factor for Oral Mucositis Induced by Intensive Chemotherapy with Hematopoietic Stem Cell Transplantation: Final Analysis of a Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial]]> https://www.researchpad.co/article/5989da80ab0ee8fa60b9a730

The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for oral mucositis (OM) induced by intensive chemotherapy with hematopoietic stem cell transplantation. In this phase 2 study, patients were randomized to either rhEGF (50 microg/mL) or placebo in a 1:1 ratio. The primary endpoint was incidence of National Cancer Institute (NCI) grade ≥2 OM. A total of 138 patients were enrolled in this study. In the intention-to-treat analysis, rhEGF did not reduce the incidence of NCI grade ≥2 OM (p = 0.717) nor reduce its duration (p = 0.725). Secondary endpoints including the day of onset and duration of NCI grade ≥2 OM, the incidence of NCI grade ≥3 OM and its duration, and patient-reported quality of life were also similar between the two groups. In the per-protocol analysis, however, the duration of opioid analgesic use was shorter in the rhEGF group (p = 0.036), and recipients in the rhEGF group required a lower cumulative dose of opioid analgesics than those in the placebo group (p = 0.046), among patients with NCI grade ≥2 OM. Adverse events were mild and transient. This study found no evidence to suggest that rhEGF oral spray reduces the incidence of OM. However, further studies are needed to investigate the effect of rhEGF on OM-induced pain reduction after intensive chemotherapy.

]]>
<![CDATA[The uniqueness of morphological features of pure erythroid leukemia in myeloid neoplasm with erythroid predominance: A reassessment using criteria revised in the 2016 World Health Organization classification]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdca8c

We reviewed 97 consecutive cases of myeloid neoplasm with erythroid predominance (MN-EP) between 2000 and 2015. Following 2016 WHO classification, MN-EP patients were classified into four groups. Eight pure erythroid leukemia (PEL) (including t-MN and AML-MRC morphologically fulfilled criteria for PEL) patients had dismal outcomes (median OS: 1 month) and showed more bone marrow fibrosis, worse performance status (PS) and higher serum lactate dehydrogenase (LDH) at diagnosis than the other groups. In the univariate analysis, risks of death in MN-EP patients included the morphologic features of PEL, very poor cytogenetic risk by IPSS-R, bone marrow fibrosis, leukocytosis, anemia, hypoalbuminemia, high LDH, and poor PS. In the multivariate analysis, independent predictors of death were morphologic features of PEL (adjusted hazards ratio [HR] 3.48, 95% confidence interval [CI] 1.24–9.74, p = 0.018), very poor cytogenetic risk by IPSS-R (adjusted HR 2.73, 95% CI 1.22–6.10, p = 0.015), hypoalbuminemia (< 3.7 g/dl) (adjusted HR 2.33, 95% CI 1.10–4.91, p = 0.026) and high serum LDH (≥ 250 U/L) (adjusted HR 2.36, 95% CI 1.28–4.36, p = 0.006). Poor or unfavorable risk in different cytogenetic risk systems independently predicted death and UKMRC-R was the best model.

]]>
<![CDATA[VH1 Family Immunoglobulin Repertoire Sequencing after Allogeneic Hematopoietic Stem Cell Transplantation]]> https://www.researchpad.co/article/5989db49ab0ee8fa60bd981d

After allogeneic hematopoietic stem cell transplantation (HSCT), recovery of humoral immunity is essential to protect from life-threatening infections. However, monitoring the humoral immune system after transplantation with standard techniques in the clinical routine is imprecise. Here, we performed sequencing of mononuclear bone marrow cells to characterize the VH1-repertoire of switched B cells of healthy volunteers and patients undergoing HSCT. Analysis of healthy bone marrow donors and patients showed virtually no clonally related sequences between individuals. Interestingly, clonally related sequences were present in pre- and post-transplantation bone marrow of patients undergoing HSCT for acute myeloid leukemia treatment. We consistently observed such related B cell clones, irrespective of conditioning regimen, donor source or time post transplantation. In general, repertoire diversity was lower in post-HSCT as compared to pre-HSCT samples. However, post-HSCT repertoires retained highly mutated sequences, despite immunosuppressive therapy and presence of T cell deficiency after HSCT. These observations identify key properties of the recovering B cell compartment and provide a conceptual framework for the surveillance of humoral immunity after allogeneic transplantation.

]]>
<![CDATA[Secondary Solid Organ Neoplasm in Patients with Acute Lymphoblastic Leukemia: A Nationwide Population-Based Study in Taiwan]]> https://www.researchpad.co/article/5989da8aab0ee8fa60b9d8d0

Background

Acute lymphoblastic leukemia (ALL) is more common in children than in adults. Secondary neoplasms (SNs) in childhood ALL have been widely reported. However, only one study has demonstrated SNs in adult ALL. Because of the poorer survival of adult ALL, the incidence might be underestimated.

Objective

To evaluate the incidence and risk factors of secondary solid organ neoplasms among adult and child ALL patients.

Methods

Newly diagnosed ALL patients between 1997 and 2011 were recruited from the Taiwan National Health Insurance database. Those who had antecedent or combined malignancies were excluded. Standardized incidence ratios (SIRs) were analyzed to compare the risk of our cohort to general population in the same age, sex and calendar year. Risk factors for SN development were analyzed by Cox proportional hazards models. Effects of treatments were treated as time-dependent variables.

Results

The 15-year cumulative incidence of SN was 1.9% and 8.4% in 1,381 child and 2,154 adult ALL patients, respectively. The SIR was significantly increased in child ALL (SIR 6.06), but not in adult ALL (SIR 1.16). The SIRs of follow-up periods were 5.14, 2.24, .87 and .71 at ≥ 10 years, 5–10 years, 1–5 years and 0–1, respectively. Overall, 15 SNs developed, and CNS tumors (SIR 11.56) were the most common type. Multivariate analysis showed that age ≥ 20 years (hazard ratio [HR] 5.04), end-stage renal disease (HR 18.98) and cranial irradiation (HR 8.12) were independent risk factors for cancer development.

Conclusions

When compared with the general population, child ALL shows a increased risk of developing SNs. CNS tumors are the most common type, and cranial irradiation is an independent risk factor. With longer follow-up, the risk of SNs increases. Hence, physicians need to pay more attention on the risk of developing SNs in long-term ALL survivors with risk factors.

]]>
<![CDATA[Conjunctival Acute Graft-versus-Host Disease in Adult Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation: A Cohort Study]]> https://www.researchpad.co/article/5989dabdab0ee8fa60baf6c7

Background

To investigate the incidence, risk factors and survival of conjunctival acute graft-versus-host disease (aGVHD) in adult patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT)

Methods

This retrospective study included a total of 139 patients undergoing allogeneic HSCT between January 2012 and December 2014 at a tertiary referral hospital. Patients with ocular complaints after allogeneic HSCT or first donor lymphocyte infusion were evaluated by ophthalmologists. The risk factors for conjunctival aGVHD were analyzed using the Cox proportional hazards model. The overall survival was evaluated using Kaplan-Meier estimates.

Results

Thirteen (9.4%) patients developed conjunctival aGVHD, including eight patients with pseudomembranous conjunctivitis. The cumulative incidence of conjunctival aGVHD was 2.1 cases per 10,000 person-day. The median age at HSCT was 47 years (range, 18 to 66) in all patients and 42 years (range, 24 to 58) in the 13 patients with conjunctival aGVHD. Median time of follow-up after allogeneic HSCT was 353 days (range, 11 to 1184). In univariate analysis, grades II-IV skin aGVHD (P = 0.002) and advanced systemic aGVHD except skin aGVHD (overall grades III-IV) (P = 0.001) were significant predictors for conjunctival aGVHD. In multivariate analysis, grades II-IV skin aGVHD was a significant risk factor (P = 0.04). The severity of conjunctival aGVHD was generally correlated with the systemic aGVHD (P = 0.001). Overall survival was significantly shorter in patients with grades II-IV aGVHD compared to those with grade 0-I (P = 0.01). Survival in patients with conjunctival aGVHD did not differ significantly from those without this complication (P = 0.94). In the subgroup analysis of patients with grades III-IV aGVHD, survival was significantly longer in patients with conjunctival involvement than those without (P = 0.03).

Conclusions

The severity of conjunctival aGVHD is correlated with systemic aGVHD, but not with inferior overall survival.

]]>
<![CDATA[Human Adenovirus-Specific γ/δ and CD8+ T Cells Generated by T-Cell Receptor Transfection to Treat Adenovirus Infection after Allogeneic Stem Cell Transplantation]]> https://www.researchpad.co/article/5989da79ab0ee8fa60b97ed1

Human adenovirus infection is life threatening after allogeneic haematopoietic stem cell transplantation (HSCT). Immunotherapy with donor-derived adenovirus-specific T cells is promising; however, 20% of all donors lack adenovirus-specific T cells. To overcome this, we transfected α/β T cells with mRNA encoding a T-cell receptor (TCR) specific for the HLA-A*0101-restricted peptide LTDLGQNLLY from the adenovirus hexon protein. Furthermore, since allo-reactive endogenous TCR of donor T lymphocytes would induce graft-versus-host disease (GvHD) in a mismatched patient, we transferred the TCR into γ/δ T cells, which are not allo-reactive. TCR-transfected γ/δ T cells secreted low quantities of cytokines after antigen-specific stimulation, which were increased dramatically after co-transfection of CD8α-encoding mRNA. In direct comparison with TCR-transfected α/β T cells, TCR-CD8α-co-transfected γ/δ T cells produced more tumor necrosis factor (TNF), and lysed peptide-loaded target cells as efficiently. Most importantly, TCR-transfected α/β T cells and TCR-CD8α-co-transfected γ/δ T cells efficiently lysed adenovirus-infected target cells. We show here, for the first time, that not only α/β T cells but also γ/δ T cells can be equipped with an adenovirus specificity by TCR-RNA electroporation. Thus, our strategy offers a new means for the immunotherapy of adenovirus infection after allogeneic HSCT.

]]>
<![CDATA[Autologous hematopoietic stem cell transplantation in lymphoma patients is associated with a decrease in the double strand break repair capacity of peripheral blood lymphocytes]]> https://www.researchpad.co/article/5989db51ab0ee8fa60bdc24b

Patients who undergo autologous hematopoietic stem cell transplantation (aHCT) for treatment of a relapsed or refractory lymphoma are at risk of developing therapy related- myelodysplasia/acute myeloid leukemia (t-MDS/AML). Part of the risk likely resides in inherent interindividual differences in their DNA repair capacity (DRC), which is thought to influence the effect chemotherapeutic treatments have on the patient’s stem cells prior to aHCT. Measuring DRC involves identifying small differences in repair proficiency among individuals. Initially, we investigated the cell model in healthy individuals (primary lymphocytes and/or lymphoblastoid cell lines) that would be appropriate to measure genetically determined DRC using host-cell reactivation assays. We present evidence that interindividual differences in DRC double-strand break repair (by non-homologous end-joining [NHEJ] or single-strand annealing [SSA]) are better preserved in non-induced primary lymphocytes. In contrast, lymphocytes induced to proliferate are required to assay base excision (BER) or nucleotide excision repair (NER). We established that both NHEJ and SSA DRCs in lymphocytes of healthy individuals were inversely correlated with the age of the donor, indicating that DSB repair in lymphocytes is likely not a constant feature but rather something that decreases with age (~0.37% NHEJ DRC/year). To investigate the predictive value of pre-aHCT DRC on outcome in patients, we then applied the optimized assays to the analysis of primary lymphocytes from lymphoma patients and found that individuals who later developed t-MDS/AML (cases) were indistinguishable in their DRC from controls who never developed t-MDS/AML. However, when DRC was investigated shortly after aHCT in the same individuals (21.6 months later on average), aHCT patients (both cases and controls) showed a significant decrease in DSB repair measurements. The average decrease of 6.9% in NHEJ DRC observed among aHCT patients was much higher than the 0.65% predicted for such a short time frame, based on ageing results for healthy individuals.

]]>
<![CDATA[Maintenance of Leukemia-Initiating Cells Is Regulated by the CDK Inhibitor Inca1]]> https://www.researchpad.co/article/5989da3fab0ee8fa60b89791

Functional differences between healthy progenitor and cancer initiating cells may provide unique opportunities for targeted therapy approaches. Hematopoietic stem cells are tightly controlled by a network of CDK inhibitors that govern proliferation and prevent stem cell exhaustion. Loss of Inca1 led to an increased number of short-term hematopoietic stem cells in older mice, but Inca1 seems largely dispensable for normal hematopoiesis. On the other hand, Inca1-deficiency enhanced cell cycling upon cytotoxic stress and accelerated bone marrow exhaustion. Moreover, AML1-ETO9a-induced proliferation was not sustained in Inca1-deficient cells in vivo. As a consequence, leukemia induction and leukemia maintenance were severely impaired in Inca1−/− bone marrow cells. The re-initiation of leukemia was also significantly inhibited in absence of Inca1−/− in MLL—AF9- and c-myc/BCL2-positive leukemia mouse models. These findings indicate distinct functional properties of Inca1 in normal hematopoietic cells compared to leukemia initiating cells. Such functional differences might be used to design specific therapy approaches in leukemia.

]]>
<![CDATA[Cardiometabolic risk factors and health behaviors in family caregivers]]> https://www.researchpad.co/article/5989db5aab0ee8fa60bdf5cf

The purpose of this study was to compare components of cardiometabolic risk and health behaviors of 20 family caregivers of allogeneic hematopoietic stem cell transplant patients to those of age, gender, and race/ethnicity-matched controls. A prospective, repeated measures design was used to compare cardiometabolic risk and health behaviors in caregivers and controls at three time-points: pre-transplantation, discharge, and six weeks post-discharge. Measures included components of metabolic syndrome, Reynolds Risk Score, NMR serum lipoprotein particle analyses, and the Health-Promoting Lifestyle Profile II (HPLP-II). Mixed-model repeated measure analyses were used. There were no between or within group differences in LDL cholesterol, HDL cholesterol, and triglycerides. There was a significant interaction effect between time and role in large VLDL concentration (VLDL-P) (F (2, 76) = 4.36, p = .016), with the trajectory of large VLDL-P increasing over time in caregivers while remaining stable in controls. Within caregivers, VLDL particle size (VLDL-Z) was significantly larger at time-point three compared to time-points one (p = .015) and two (p = .048), and VLDL-Z was significantly larger in caregivers than in controls at time point three (p = .012). HPLP-II scores were lower in caregivers than controls at all time-points (p < .01). These findings suggest that caregiving may have a bigger impact on triglycerides than on other lipids, and it is through this pathway that caregivers may be at increased cardiometabolic risk. More sensitive measurement methods, such as NMR lipoprotein particle analyses, may be able to detect early changes in cardiometabolic risk.

]]>