No Association of AS3MT Gene Polymorphisms with Susceptibility to Hepatotoxicity in APL Patients Treated with AS2O3: A Single-Center Study.

Background: Arsenic three oxide (As2O3) is the treatment choice for acute promyelocytic leukemia (APL). Little is known about possible risk factors with predictive value for toxicity caused by As2O3. Biomethylation is considered to be a major pathway of detoxification for inorganic arsenics (iAs). Arsenic Methyltransferase (AS3MT) is one of the key enzymes involved in the transfer of a methyl group from S-adenosyl-L-methionine to trivalent arsenical and plays a critical role in arsenic detoxification. Polymorphisms in hAS3MT lead to a change in the catalytic activity of the enzyme and may increase the risk of arsenic-related toxicity. In this study, we investigated the association of the AS3MT polymorphisms (rs11191439, rs3740390, and rs3740393) genes with hepatotoxicity in APL patients treated with As2O3. Materials and Methods: Genotyping was performed in 140 adult patients with APL treated with As2O3 using PCR-RFLP for rs11191439 and tetra-primer ARMS-PCR for rs3740390 and rs3740393. The results of PCR-RFLP and ARMS-PCR were confirmed by direct sequencing of 10 % of DNA samples. The results were analyzed using SNPStats, SPSS, and FinchTV. Hepatotoxicity was graded according to the National Cancer Institute's Common Toxicity Criteria (CTC). Results : Hepatotoxicity was seen in 52 of the 140 patients (37.1%), with grades I and II hepatotoxicity in 40 (28.6%) and grades III and IV hepatotoxicity in 12 (8.5%) patients. The association between the three polymorphisms and hepatotoxicity was evaluated using five genetic models and none of the three studied polymorphisms were significantly associated with hepatotoxicity. Discussion : The results of our study showed that AS3MT rs11191439, rs3740390, and rs3740393 polymorphisms are not associated with hepatotoxicity in APL patients. Genetic polymorphisms in enzymes which are involved in arsenic metabolism have been shown to have ethnicity and race-related differences. To more precisely characterize the association between AS3MT gene polymorphism and hepatotoxicity, future large-scale studies in non-Asian populations and other ethnicities are needed.

Phase I non-randomized clinical trial of allogeneic natural killer cells infusion in acute myeloid leukemia patients.

INTRODUCTION: A new type of immune cell transplantation called allogeneic NK cell infusion is proposed as a potential universal off-the-shelf cell product for adoptive immune cell therapy in hematologic malignancies. DESIGN: A multicentral phase I non-randomized clinical trial was conducted to assess the safety, feasibility, and potential efficacy of adoptively infused NK cells in patients with refractory/relapsed AML. We evaluated the feasibility of the trial by considering cell production, patient selection, and treatment protocol. METHOD: Allogeneic NK cells were produced from random healthy unrelated donors; 10 patients were selected according to the inclusion criteria and were included in two groups in case of NK cell dose escalation. Two cell infusions were given, spaced 7 days apart, following a lymphodepletion conditioning regimen of fludarabin-endoxan administered 7 days before the first infusion. The intervention safety was scored using Common Terminology Criteria for Adverse Events (CTCAE) based on variations in vital signs due to cell infusion. NK cell chimerism, tumor burden, and duration of relapse were considered to be components of efficacy. The pilot feasibility evaluation was checked using the CONSORT platform. RESULTS: The NK cell infusion procedure was well tolerated, and no grade 2-5 toxicities related (possible or probable) to PB-NK cell infusion were observed. Four patients developed grade 1 transient chills, headaches, vomiting, and bone pain following each PB-NK cell infusion that were not required hospitalization. One of these patients (p01) died because of severe acute respiratory syndrome. Of 9 evaluable patients, 6 (66.6%) showed stable disease (SD) and 3 (33.3%) presented progressive disease (PD). Of 6 SD patients, 2 (p08 and p09) remained alive in SD and 3 patients (p04, p05 and p07) converted to PD at 9 months after infusion of NK cells, and 1 (p03) was not evaluable due to follow-up loss. No patient achieved complete remission. CONCLUSION: The study demonstrated the feasibility and safety of adoptive transfer of random healthy unrelated donor PB-NK cells in refractory/relapsed AML patients and supports continued study in phase II clinical trials in relapsed/refractory AML patients.

FAT1 Gene Expression in Iranian Acute Lymphoid and Myeloid Leukemia Patients.

BACKGROUND: FAT atypical cadherin 1 (FAT1) is a member of the cadherin superfamily whose loss or gain is associated with the initiation and/or progression of different cancers. FAT1 overexpression has been reported in hematological malignancies. This research intended to investigate FAT1 gene expression in adult Iranian acute leukemia patients, compared to normal mobilized peripheral blood CD34+ cells. MATERIALS AND METHODS: The peripheral blast (peripheral blood mononuclear cells) cells of 22 acute myeloid leukemia (AML), 14 acute lymphoid leukemia (ALL) patients, and mobilized peripheral blood CD34+ cells of 12 healthy volunteer stem cell donors were collected. Then, quantitative real-time polymerase chain reaction (qPCR) was used to compare FAT1 gene expression. RESULTS: Overall, there were no significant differences in FAT1 expression between AML and ALL patients (p>0.2). Nonetheless, the mean expression level of FAT1 was significantly higher in leukemic patients (AML and ALL) than in normal CD34+ cells (p=0.029). Additionally, the FAT1 expression levels were significantly higher in both CD34+ and CD34- leukemic patients than in normal CD34+ cells (p=0.028). CONCLUSION: No significant differences were found between FAT1 expression in CD34+ and CD34- leukemic samples (p> 0.3). Thus, higher FAT1 expression was evident in ALL and AML leukemia cells but this appeared unrelated to CD34 expression. This suggests in a proportion of adult acute leukemia, FAT1 expression may prove to be a suitable target for therapeutic strategies.

Safety and feasibility study of ex vivo expanded allogeneic-NK cells infusion in patients with acute pneumonia caused by COVID-19.

BACKGROUND: NK cells are the most active innate immune cells in antiviral immunity, which are impaired by SARS-COV2 infection. Infusion of allogeneic NK cells might be a complementary treatment to boost immune system function in COVID-19 patients. In this project, we focused on COVID-19 patients with low inspiratory capacity (LIC). This project aims to evaluate the feasibility and safety of allogeneic NK cell infusion as an intervention for respiratory viral disease. METHODS: A non-blind two arms pilot study was designed and conducted after signing the consent form. Ten matched patients, in terms of vital signs and clinical features, were enrolled in the control and intervention groups. Approximately 2 × 10^6 cells/kg of NK cells were prepared under GCP (good clinical practice) conditions for each patient in the intervention group. The control group was under the same conditions and drug regimen except for the treatment with the prepared cells. Then, infused intravenously during 20 min in the ICU ward of Masih Daneshvari Hospital. The clinical signs, serological parameters, and CTCAE (Common Terminology Criteria for Adverse Events) were recorded for safety evaluation and the feasibility of project management were evaluated via designed checklist based on CONSORT. RESULTS: There were no symptoms of anaphylaxis, hypersensitivity, significant changes in blood pressure, cardiovascular complications, and fever from injection time up to 48 h after cell infusion. The mean hospitalization period in the control and intervention groups was 10 and 8 days, respectively. The blood O2 saturation level was raised after cell infusion, and a significantly lower mean level of inflammatory enzymes was observed in the intervention group following discharge compared to the control group (p < 0.05). The inflammatory parameters differences at the discharge date in cell therapy group were highly negative. CONCLUSION: Intravenous infusion of ex vivo-expanded allogeneic NK cells was safe and feasible. However, the efficacy of this approach to reducing the severity of disease in COVID-19 patients with LIC could not be determined. TRIAL REGISTRATION: Name of the registry: NKCTC. IRCT20200621047859N2. December 29, 2020. URL of trial registry record: https://www.irct.ir/trial/49382.

Three doses of a recombinant conjugated SARS-CoV-2 vaccine early after allogeneic hematopoietic stem cell transplantation: predicting indicators of a high serologic response-a prospective, single-arm study.

Background: Allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients must be vaccinated against SARS-CoV-2 as quickly as possible after transplantation. The difficulty in obtaining recommended SARS-CoV-2 vaccines for allo-HSCT recipients motivated us to utilize an accessible and affordable SARS-CoV-2 vaccine with a recombinant receptor-binding domain (RBD)-tetanus toxoid (TT)-conjugated platform shortly after allo-HSCT in the developing country of Iran. Methods: This prospective, single-arm study aimed to investigate immunogenicity and its predictors following a three-dose SARS-CoV-2 RBD-TT-conjugated vaccine regimen administered at 4-week (± 1-week) intervals in patients within 3-12 months post allo-HSCT. An immune status ratio (ISR) was measured at baseline and 4 weeks (± 1 week) after each vaccine dose using a semiquantitative immunoassay. Using the median ISR as a cut-off point for immune response intensity, we performed a logistic regression analysis to determine the predictive impact of several baseline factors on the intensity of the serologic response following the third vaccination dose. Results: Thirty-six allo-HSCT recipients, with a mean age of 42.42 years and a median time of 133 days between hematopoietic stem cell transplant (allo-HSCT) and the start of vaccination, were analyzed. Our findings, using the generalized estimating equation (GEE) model, indicated that, compared with the baseline ISR of 1.55 [95% confidence interval (CI) 0.94 to 2.17], the ISR increased significantly during the three-dose SARS-CoV-2 vaccination regimen. The ISR reached 2.32 (95% CI 1.84 to 2.79; p = 0.010) after the second dose and 3.87 (95% CI 3.25 to 4.48; p = 0.001) after the third dose of vaccine, reflecting 69.44% and 91.66% seropositivity, respectively. In a multivariate logistic regression analysis, the female sex of the donor [odds ratio (OR) 8.67; p = 0.028] and a higher level donor ISR at allo-HSCT (OR 3.56; p = 0.050) were the two positive predictors of strong immune response following the third vaccine dose. No serious adverse events (i.e., grades 3 and 4) were observed following the vaccination regimen. Conclusions: We concluded that early vaccination of allo-HSCT recipients with a three-dose RBD-TT-conjugated SARS-CoV-2 vaccine is safe and could improve the early post-allo-HSCT immune response. We further believe that the pre-allo-HSCT SARS-CoV-2 immunization of donors may enhance post-allo-HSCT seroconversion in allo-HSCT recipients who receive the entire course of the SARS-CoV-2 vaccine during the first year after allo-HSCT.

Novel delivery of sorafenib by natural killer cell-derived exosomes-enhanced apoptosis in triple-negative breast cancer.

Aim: We investigated the delivery of sorafenib (SFB) to breast cancer spheroids by natural killer cell-derived exosomes (NK-Exos). Methods: SFB-NK-Exos were constructed by electroporation. Their antitumor effects were evaluated by methyl thiazolyl tetrazolium, acridine orange/ethidium bromide, 4',6-diamidino-2-phenylindole, annexin/propidium iodide, scratch and migration assay, colony formation, RT-PCR, western blot and lipophagy tests. Result: The loading efficacy was 46.66%. SFB-NK-Exos-treated spheroids showed higher cytotoxic effects (33%) and apoptotic population (44.9%). Despite the reduction of SFB concentration in the SFB-NK-Exos formulation, similar cytotoxic effects to those of free SFB were observed. Increased intracellular trafficking, sustained release of the drug and selective inhibitory effects demonstrated efficient navigation. Conclusion: This is the first report for SFB loading into NK-Exos, which led to significant cytotoxic intensification against cancer cells.

What is this summary about? This study describes the delivery of an anticancer drug called sorafenib (SFB) to laboratory-grown spherical masses of cancer cells called spheroids. Saucer-like cellular structures called exosomes were used as drug-delivery tools. These exosomes were produced by a subgroup of immune cells called natural killer (NK) cells. NK cells are responsible for killing cancer cells. So, these exosomes share similar anticancer properties with NK cells. We wanted to test whether exosomes loaded with SFB would have better anticancer effects. What were the results? Using different methods, SFB was loaded within the exosomes and delivered to the spheroids. The obtained results showed that a combination of exosomes and SFB could improve the targeting efficacy, reducing the side effects to the normal cells and allowing continuous release of the drug. The spheroids were killed with higher efficacy following this treatment. What do the results of the study mean? The combination of NK cell-derived exosomes and SFB could lead to better cytotoxicity against cancer cells. Therefore, this strategy could have better anticancer effects compared with SFB treatment alone.

Comparable Outcomes of Pre- Versus Post-Tyrosine Kinase Inhibitor Era Treatment in Chronic Myeloid Leukemia: A Retrospective Cohort Study With Long-term Follow-up.

Imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was introduced after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with chronic myeloid leukemia (CML). However, the long-term effects of allo-HSCT in chronic phase CML patients are mostly unknown. We retrospectively analyzed the outcomes of 204 patients with sibling donors who received peripheral stem cells and underwent allo-HSCT of chronic phase I (CP1) in the pre- and post-TKI era at Shariati Hospital in Tehran, Iran, from 1998 to 2017 and followed up till the end of 2021. The median follow-up time for all patients was 8.7 (SD = 0.54) years. Fifteen-year overall survival (OS), disease-free survival (DFS), graft-versus-host disease-free relapse-free survival (GRFS), relapse, and non-relapse mortality (NRM) incidence were 65.70%, 57.83%, 17.56%, 13.17%, and 28.98%, respectively. Using multivariable analyses, the only risk factor increasing the hazard of death was the time between diagnosis to allo-HSCT greater than 1 year compared to this time less than 1 year by 74% [hazard ratio (HR) = 1.74, P = 0.039]. Also, age is a significant risk factor for DFS (HR = 1.03, P = 0.031). Our findings suggested that allo-HSCT is still an important treatment option for CP1 patients, especially those resistant to TKI treatment. TKI consumption can have a desirable effect on NRM after allo-HSCT for CP1 CML.

Cardiovascular diseases in patients after hematopoietic stem cell transplantation: Systematic review and Meta-analysis.

BACKGROUND: Hematopoietic Stem Cell Transplantation (HSCT), is performed to treat many malignancies such as autologous or allogenic. Despite the success of this method in treating patients, - sometimes some HSCT recipients face problems such as cardiovascular complications. Therefore, this systematic review and meta-analysis aimed to evaluate the prevalence of cardiovascular complications in post-transplant patients. METHOD: In order to review the published studies, we examined PubMed, MEDLINE, Cochrane Library, Scopus, and web of science databases from the beginning to the end of January 2022, and we used tools by the Newcastle-Ottawa Scale to evaluate the quality of the studies. RESULT: In this study, 37 articles were included in the meta-analysis and 30,957 patients were examined. Also, the mean age of patients was 35.37 years. Based on the results of the meta-analysis, the prevalence of cardiovascular disease (CVD), was 16.84%. In addition, other complications related to CVD which include Arrhythmias, Congestive Heart Failure (CHF), Hypertension, stroke, and mortality were examined in patients who had hematopoietic stem cell transplantation and the resulting amounts were 3.91%, 3.66, 17.71, 0.22%, and 1.53%, respectively. CONCLUSION: This study showed that the prevalence of cardiovascular disease after hematopoietic stem cell transplantation is high and needs special attention.

Incidence and Prognostic Impact of WT-1 Gene Exon7 and 9 Mutations in Acute Promyelocytic Leukemia.

Background: Wilms' tumor suppressor gene 1 (WT1) gene mutation has been reported to be a prognostic factor in normal-cytogenetic acute myeloid leukemia (AML) patients. Higher rates of mutation in the WT1 gene have been reported in several tumors including normal-cytogenetic AML patients. Data regarding WT1 mutations in acute promyelocytic leukemia (APL) is very scarce. In this study, we evaluated the incidence and impact of WT1 mutation on the outcome of APL patients. Materials and Methods: A total of 92 patients diagnosed with APL were studied in three distinct groups: early mortality, relapsed, and persistent complete remission. Genomic DNA of bone marrow samples of patients was analyzed. For quantification of expression levels of the WT1 gene, real-time quantitative PCR (rqPCR) was performed by a real-time PCR system. WT1 mutation and its impact on prognosis were considered the primary endpoint of the study. Statistical analysis was performed with STATA. Results: WT1 mutation frequency was 6.25% in the early mortality group (1/16 patients), 13.16% in the relapse group (5/38 patients), and 7.89% in the persistent complete remission group (3/38 patients). 8 mutations were in exon 7 and one mutation in exon 9. WT1 mutation in the relapse group was associated with a trend toward worse disease-free survival (DFS) while overall survival (OS) was not affected by WT1 mutation in univariate analysis. Patients with no mutations in WT1 and FLT3/ITD had better overall survival and disease-free survival compared to patients with mutations in the WT1 gene or FLT3/ITD in the relapse group. Conclusion: The frequency of WT1 gene mutations does not differ significantly between patients with early mortality, relapse, and persistent complete remission. The presence of WT1 mutation is associated with higher relapse and lower survival rates in relapse group patients.

A Comparison of Dexamethasone Plus Vincristine versus Standard Regimen in Induction Therapy of Adult Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplantation.

Background: Current treatment options of acute lymphoblastic leukemia(ALL) include chemotherapy alone or hematopoietic stem cell transplantation (HSCT) following induction chemotherapy both along with CNS prophylaxis. The usual and standard induction regimens currently administered could have severe complications and mortality. Materials and Methods: To lessen induction regimen complications in ALL patients who undergo HSCT, we used a cytoreduction induction regimen including dexamethasone (8 mg, IV, three times a day, for 28 days) and vincristine(1.4 mg/m2, IV, on days 1,8,15 and 22) for 49 newly diagnosed adult ALL patients followed by an early sibling donor HSCT within two months. The results were matched with outcomes of HSCT in 172 ALL patients inducted by standard induction regimen. Results: Median follow-up time was 5.41 years in the standard group and 5.27 years in the other. All patients of the case group (100%) achieved complete remission. Landmark analyses were performed to scrutinize the effect of treatments on different time intervals: first two years and 2nd to end years. Type of treatment had no significant effect on the hazard of death in the first landmark (HR=0.87, P=0.64). Cytoreduction regimen amplified the hazard of death 3.43 times more than the standard regimen in the second landmark (HR=3.43 P=0.035). Multivariate analysis showed that the cytoreduction regimen reduced the hazard of relapse about 22%, but not statistically significant (HR=0.78, P-value=0.24). Conclusion: Overall, it seems despite achieving complete remission in induction therapy, depth of response is a critical predictor for long-term outcomes of HSCT in ALL patients, and the use of multiple agents may be necessary to decrease tumor cell burden and minimal residual disease(MRD).

Modified combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) as compared with standard ATG protocol in haploidentical peripheral blood stem cell transplantation for acute leukemia.

In haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), the combination of anti-thymocyte globulin and post-transplant cyclophosphamide (ATG/PTCy) has a synergistic impact in preventing graft-versus-host disease (GvHD). However, little is known about the long-term consequences of the new combination approach. Our goal is to evaluate the efficacy of ATG/PTCy versus a standard ATG regimen by focusing at long-term outcomes in a more homogeneous group of patients. We retrospectively included 118 adult patients up to 60 years with acute leukemia who underwent haplo-PBSCT at our single institution, following the same myeloablative conditioning regimen. From 2010 to 2020, 78 patients received a modified combination of ATG (2.5 mg/kg/day, on days -3, -2, and -1) and PTCy (40 mg/kg/day on days +3 and +4) compared to 40 patients who had a standard ATG-based regimen (2.5 mg/kg/day from days -4 to -1) from 2008 to 2015. The median follow-up time for all patients was 5.36 years, respectively. The cumulative incidence (CI) of neutrophil and platelet engraftment, as well as CMV reactivation, did not differ statistically between the two groups. The CI of the acute GvHD of grades II-IV and III-IV and extensive chronic GvHD were considerably lower in the ATG/PTCy (34.6%, 8.97%, and 13.63%) than in the ATG cohort (57.5%, 30%, and 38.23%) as validated by multivariable modeling. Additionally, compared to the ATG arm, the ATG/PTCy was a hazard factor associated with a higher risk of relapse (HR = 2.23, p = 0.039). The probability of 5-year overall survival, disease-free survival, and GvHD-free relapse-free survival in the ATG/PTCy group (53.34%, 49.77%, and 36.04%) was comparable with the ATG group (47.5%, 42.5%, and 22.5%), respectively. Our finding suggested that a modified ATG/PTCy combination resulted in a lower risk of acute and chronic GvHD and a higher risk of relapse than the standard ATG-based protocol but had no effect on long-term outcomes. However, certain adjustments in the immunosuppression protocol are warranted to improve the outcome.

Human placenta-derived mesenchymal stem cells transplantation in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 (phase I clinical trial): safety profile assessment.

BACKGROUND: High morbidity and mortality rates of the COVID-19 pandemic have made it a global health priority. Acute respiratory distress syndrome (ARDS) is one of the most important causes of death in COVID-19 patients. Mesenchymal stem cells have been the subject of many clinical trials for the treatment of ARDS because of their immunomodulatory, anti-inflammatory, and regenerative potentials. The aim of this phase I clinical trial was the safety assessment of allogeneic placenta-derived mesenchymal stem cells (PL-MSCs) intravenous injection in patients with ARDS induced by COVID-19. METHODS: We enrolled 20 patients suffering from ARDS caused by COVID-19 who had been admitted to the intensive care unit. PL-MSCs were isolated and propagated using a xeno-free/GMP compliant protocol. Each patient in the treatment group (N = 10) received standard treatment and a single dose of 1 × 106 cells/kg PL-MSCs intravenously. The control groups (N = 10) only received the standard treatment. Clinical signs and laboratory tests were evaluated in all participants at the baseline and during 28 days follow-ups. RESULTS: No adverse events were observed in the PL-MSC group. Mean length of hospitalization, serum oxygen saturation, and other clinical and laboratory parameters were not significantly different in the two groups (p > 0.05). CONCLUSION: Our results demonstrated that intravenous administration of PL-MSCs in patients with COVID-19 related ARDS is safe and feasible. Further studies whit higher cell doses and repeated injections are needed to evaluate the efficacy of this treatment modality. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT); IRCT20200621047859N4. Registered 1 March 2021, https://en.irct.ir/trial/52947 .

Outcomes of haploidentical peripheral stem cell transplantation with combination of post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) compared to unrelated donor transplantation in acute myeloid leukemia: A retrospective 10-year experience.

In the evolution of haploidentical hematopoietic stem cell transplantation (haplo-HSCT), In vivo T-cell modulation with concomitant use of anti-thymocyte globulin (ATG) and high-dose post-transplant cyclophosphamide (PTCy) provides a novel promising method on transplant outcomes; however, the long-term effects of this therapy are mostly unknown. We retrospectively compared the long-term outcomes of adult acute myeloid leukemia (AML) patients undergoing a haplo-HSCT (n = 92) with a new modified combination of ATG and PTCy in the context of peripheral blood stem cell (PBSC) and myeloablative conditioning (MAC) with an otherwise similar group of AML patients who received an unrelated donor (URD) HSCT (n = 57) with ATG protocol from February 2010 to December 2020 at our single-center (HORCSCT). Median follow-up was 3.73 and 4.28 years for haploidentical and URD-HSCT, respectively. In haplo-HSCT, the cumulative incidence of grades II-IV and III-IV acute graft versus host disease (aGvHD) and extensive chronic GvHD (cGvHD) was much lower than in URD (27% versus 56% for grades II-IV, 8.7% versus 24.5% for grades III-IV, and 15.4% versus 34.7% for extensive cGvHD, respectively). Five-year overall survival (OS) was 54.03% for haplo and 54.48% for URD (p = 0.927); GvHD-free relapse-free survival (GRFS) was 44.1% and 29.86% (p = 0.149); relapse incidence was 15.79% and 26.95% (p = 0.72); and non-relapse mortality (NRM) was 29.48% and 26.32% (p = 0.73), respectively. Using multivariable analyses, when compared to Haplo, URD was a significant predictor of relapse (HR=1.80, p = 0.039); however, no difference in OS, GRFS, and NRM was noted between haplo and URD. Therefore, given the favorable results with haplo-HSCT and considering donor availability promptly with low cost, it conservatively suggested that haplo-HSCT with the introduced protocol could be viewed as the first alternative for patients with AML in the absence of matched sibling donors.

Studying the potential of upregulated PTGS2 and VEGF-C besides hyper-methylation of PTGS2 promoter as biomarkers of Acute myeloid leukemia.

Hereby, we aimed to investigate the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) and Vascular Endothelial Factor-C (VEGF-C) besides the methylation of PTGS2 in AML patients. VEGF-C and PTGS2 expression analysis were evaluated in newly diagnosed AML patients and healthy controls by quantitative Reverse Transcriptase PCR method. Also, PTGS2 methylation status was evaluated by Methylation-Sensitive High-Resolution Melting Curve Analysis (MS-HRM). While 34% of patients were female, the mean age of the patients was 43.41 ± 17.60 years suffering mostly from M4 (48.21%) type of AML. Although methylation level between patients and controls was not significantly different, none of the normal controls showed methylation in the PTGS2 promoter. PTGS2 and VEGF-C levels were elevated in AML cases and correlated with WBC, Platelet, and Hemoglobin levels. The survival of patients with overexpressed VEGF-C and PTGS2 was poorer than others. It can be concluded that PTGS2 and especially VEGF-C expression but not PTGS2 methylation can be considered as diagnostic biomarkers for AML.

Radiation-free reduced-intensity hematopoietic stem cell transplantation with in vivo T-cell depletion from matched related and unrelated donors for Fanconi anemia: prognostic factor analysis.

Fanconi anemia (FA) is a rare and complex genetic disorder, clinically characterized by bone marrow failure, congenital defects, and cancer predisposition. Hematopoietic stem cell transplantation (HSCT) represents the only therapeutic option to restore normal hematopoiesis after the occurrence of marrow failure or clonal hematopoietic abnormality. However, radiation exposure during transplant may increase the risk of later malignancies. In this retrospective study, we analyzed the results of HSCT with a radiation-free, busulfan-based conditioning regimen in FA patients. A total of 122 patients (median age: 8 years, range: 2-18 years) with FA who underwent HSCT between January 2008 and January 2020 were enrolled in this study and followed up to the end of 2020. The preparative regimen included busulfan (0.2 mg/kg/day, days -9 to -6), cyclophosphamide (15 mg/kg/day, days -5 to -2), and in vivo T-cell depletion with rabbit anti-thymocyte globulin. All patients received graft-versus-host disease prophylaxis with cyclosporine combined with methotrexate. We used the Kaplan-Meier method, log-rank test, and Cox proportional hazards models to analyze patient survival. Peripheral blood, bone marrow and cord blood hematopoietic stem cells were used in 84 (68.9%), 31 (25.4%) and 7 (5.7%) patients, respectively. Donors were matched siblings in 48 (39.3%), matched other relatives in 56 (45.9%), and matched unrelated persons in 18 (14.8%) patients. With a median follow-up time of 24.25 months, graft rejection occurred in only one patient. The 1- and 5-year overall survival rates were 84.14% (95% confidence interval: 76.02-89.70) and 82.16% (95% confidence interval: 73.01-88.45), respectively. Of the patient characteristics documented before transplant, the presence of cardiopulmonary, genitourinary tract, central nervous system, and limb malformations significantly affected survival rates. Our results indicate excellent outcomes in patients with FA undergoing HSCT with a radiation-free, busulfan-based conditioning regimen. It would be desirable to aim at optimizing the outcome of HSCT in FA patients in future studies.

A fludarabine and melphalan reduced-intensity conditioning regimen for HSCT in fifteen chronic granulomatous disease patients and a literature review.

Chronic granulomatous disease (CGD) is a life-threatening immunodeficiency condition. To date, hematopoietic stem cell transplantation (HSCT) is the only curative modality. We prospectively studied the outcomes of fifteen CGD patients undergoing HSCT with fludarabine and melphalan plus anti-thymocyte globulin (ATG). Most of the donors were fully matched siblings (n = 12). Cyclosporine A and methylprednisolone were used for graft-versus-host disease (GVHD) prophylaxis. CGD diagnosis had been suspected upon clinical symptoms and was confirmed in all patients by an abnormal neutrophil functional assay. The three-year overall survival (OS) and event-free survival (EFS) rates were 73.3% and 46.7%, respectively. With the median follow-up time of 33.12 months, the mean OS and EFS were 42.6 and 26.8 months; respectively. Eleven patients (73.33%) achieved full donor chimerism. Two stable mixed chimerisms with no sign of the underlying disease (13.33%) and two secondary graft failure (13.33%) occurred as well. The cumulative incidence of transplant-related mortality was 23.1% and it was two times more in adults compared with children. Three years GVHD-FS (free survival) was 57.8% in all patients and it was 70% and 42.9% in children and adults, respectively. Our results indicate that fludarabine, melphalan, and ATG have relatively favorable outcomes in CGD patients. Also, we suggest that HSCT should be performed as soon as a suitably matched donor is found.

Retrospective Evaluation of Hairy Cell Leukemia Patients: Analysis of a Long-Term Single Center Data.

Background: Hairy cell leukemia (HCL) is a distinct lymphoproliferative disorder with unique circulating lymphocyte morphology. It is now regarded as an indolent disease yet treatable with purine analogs. We are going to present a complete long-term clinical and prognostic report of our HCL patients as a large cohort in Iran. Materials and Methods: All patients diagnosed with HCL, according to the World Health Organization (WHO) criteria, were enrolled in this study. They were referred to our academic center between 1995 and 2020. Treatment with a daily cladribine regimen was initiated as indicated and patients were followed. Survival data and clinical outcomes of patients were calculated. Results: A total of 50 patients were studied (76% male). The median time to treatment was 4.8 months and complete remission was achieved in 92% of patients. Nine patients (18%) experienced relapse with a median time to relapse of 47 months. After a median follow-up of 51 months, the median OS was not reached and after 234 months, the overall survival rate was 86%. Survival was worse in patients with non-classic HCL (vHCL) compared to classic HCL. Conclusion: Our long-term follow-up data confirmed the favorable outcomes of Iranian HCL patients with cladribine and provide a useful viewpoint of the disease.

Outcome of Peripheral Blood Allogeneic Hematopoietic Stem Cell Transplantation as a Treatment Option in Patients With Severe Aplastic Anemia Between 40 and 50 Years.

The frontline treatment for patients younger than 40 years with severe aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-identical sibling donor. However, in patients with severe AA who are older than 40 years, allogeneic HSCT has been found to be associated with increased treatment-related mortality and toxicity, even when matched sibling donors are used. We report our institutional experience with allogeneic HSCT in patients with severe AA between 40 and 50 years. A total of 19 patients with severe AA were included in the study. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. The mean age of patients at the time of transplant was 43.79 years, and 57.9% were male. The mortality rate was 36.8%, attributed to infection (10.5%), relapse (15.8%), and renal failure (5.3%) in all cases. Acute graft-versus-host disease (GVHD) occurred in five patients (26.3%), and chronic GVHD occurred in two patients (10.5%). The 5-year OS was 62% and the 5-year DFS was 52%. We found that the patient's age, platelet level prior to transplantation, and the number of CD3 cells infused for each transplant were independent prognostic factors for OS, and the age and sex of the patient, graft rejection, and platelet level prior to transplantation were significant prognostic factors associated with DFS. We recommend that immunosuppressive therapy be considered as a first-line treatment in patients with severe AA who are older than 40 years. Allogeneic HSCT can be considered a valid alternative option in patients whose suppression therapy fails.

Association of Voriconazole Trough Plasma Concentration with Efficacy and Incidence of Hepatotoxicity in Iranian Patients with Hematological Malignancies.

There are conflicting data regarding the association between plasma concentration of voriconazole (VCZ) and both efficacy and safety. This study investigates the association of VCZ trough plasma level with clinical efficacy and hepatotoxicity in the Iranian population suffering hematological malignancies. This cross-sectional study was performed on adult Iranian patients (age ≥ 18 years) with hematological malignancies undergoing treatment with oral or intravenous VCZ for proven or probable invasive aspergillosis. Plasma concentrations of VCZ were measured at two time points on day 4 and 14 during the study period. A total of 60 VCZ trough concentrations of 30 patients were drawn on days 4 and 14 after the initiation of treatment. There was no definite correlation between the mean plasma concentration of VCZ and VCZ dosage (p = 0.134, r = 0.280). In multivariable model, only plasma concentration of VCZ on day 14 was associated with the incidence of hepatotoxicity (p = 0.013; OR = 1.42, 95% CI = 1.07-3.24). Plasma trough concentration neither on day 4 nor on day 14 was related to the treatment response. No significant association was observed between the mean plasma concentration of VCZ and 3-month patients' survival (p = 0.696). To conclude, VCZ trough concentration may not be a predictor of treatment response or 3-month patients' survival. However, the wide inter- and intra-patient variability of VCZ plasma concentration coupled with the observed association between VCZ trough level and the incidence of hepatotoxicity would pose the question regarding the potential benefit of VCZ concentration monitoring.