Consensus-Based Guidelines for Acute Myeloid Leukemia Management in Gulf Cooperation Council Countries: Addressing Unmet Regional Needs and the Changing AML Landscape.

PURPOSE: AML is a heterogeneous hematologic malignancy. Region-specific recommendations for AML management can enhance patient outcomes. This article aimed to develop recommendations for the Gulf Cooperation Council (GCC) countries. METHODS: Ten AML panel members from Kuwait, Oman, Qatar, and the United Arab Emirates (KOQU) participated in a modified two-round Delphi process. The panel first identified the unmet regional needs and finalized a list of core variables. Next, they voted on iterative statements drawn from international recommendations and provided feedback via a questionnaire. Consensus voting ≤70% was discussed, and additional clinical decision making statements were suggested. At round closure, a consensus vote took place on revised statements. RESULTS: The panel reached ≥97.8% consensus on AML management. The panel agreed to use international risk stratification categories for personalized treatment of AML. The presence of ≥10% blasts for recurrent genetic abnormalities was required for a diagnosis of AML. Key consensus was reached for different treatment stages. The panel noted that older patients pose a challenge because of poor cytogenetics and genetic anomalies and require different treatment approaches. The panel recommended venetoclax-hypomethylating agents; fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor; and targeted therapy for AML relapsed/refractory disease. Supportive care is considered on the basis of prevailing organisms and drug resistance. CONCLUSION: The GCC KOQU's consensus-based recommendations for managing AML include an evidence-based and region-specific framework.

Current Status and Management of Chronic Myeloid Leukemia in the Gulf Region: Survey Results and Expert Opinion.

Studies on chronic myeloid leukemia (CML) in the Gulf region are scarce, consisting of a survey and expert meeting that included 15 experts in 2023 which discussed CML diagnosis, testing, treatment objectives, toxicities, and discontinuation in the Gulf region. Most patients were reported to be in first-line therapy, and the most common treatments were imatinib/imatinib generic in first-line and dasatinib in second- and third-lines. Mutation analysis was not reported to be routinely performed at the time of diagnosis but rather in case of progression to accelerated/blast phase or any sign of loss of response. While all participants were aware that BCR-ABL should be monitored every three months during the first year of treatment, 10% reported monitoring BCR-ABL every six months in practice due to test cost and lab capability. The most important first-line therapy objective was "achievement of major molecular response" (MMR) in younger patients and "overall survival" in older ones. The most important treatment objectives were "MMR" and "early molecular response followed by prolongation of overall survival" in the short term and "treatment-free remission" in the long term. The current practices in CML in the Gulf region appear to be similar to global figures.

Immune reconstitution and survival, following hematopoietic stem cell transplantation in Omani patients with inborn errors of immunity.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity. METHODS: A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT. RESULTS: The median age at transplant was 11.0 months (4.6-61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40-100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2-13.6), 0.9 × 109/L 0.6-1.2), and 0.5 × 109/L (0.2-0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0-14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4-11.5). The 10-year overall probability of survival is 84.3%. CONCLUSION: Monitoring IRC is important in ensuring adequate disease-free survival.

The Contemporary Role of Hematopoietic Stem Cell Transplantation in the Management of Chronic Myeloid Leukemia: Is It the Same in All Settings?

Hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) patients has transitioned from the standard of care to a treatment option limited to those with unsatisfactory tyrosine kinase inhibitor (TKI) responses and advanced disease stages. In recent years, the threshold for undergoing HSCT has increased. Most CML patients now have life expectancies comparable to the general population, and therefore, the goal of therapy is shifting toward achieving treatment-free remission (TFR). While TKI discontinuation trials in CML show potential for achieving TFR, relapse risk is high, affirming allogeneic HSCT as the sole curative treatment. HSCT should be incorporated into treatment algorithms from the time of diagnosis and, in some patients, evaluated as soon as possible. In this review, we will look at some of the recent advances in HSCT, as well as its indication in the era of aiming for TFR in the presence of TKIs in CML.

Management of adult acute lymphoblastic leukemia in the Gulf Cooperation Council (GCC) countries: A consensus report from the GCC Adult ALL Working Group.

Leukemia burden is growing in the Gulf Council Cooperation (GCC) countries. Nonetheless, there is no unified protocol for managing adult acute lymphoblastic leukemia (ALL) patients in the GCC-countries. Therefore, the GCC Adult-ALL Treaters working group developed this consensus to address the adult-ALL treatment protocols in the GCC-countries and related toxicities' management. Besides, the consensus aimed to highlight the current unmet needs and treatment gaps and provide recommendations to optimize adult-ALL care and patient-centered communication. A three-step modified Delphi method to develop evidence-based recommendations through two-voting rounds and in-between virtual meetings are used in the manuscript development. A 12 experts' panel from five GCC-countries and two international experts were invited to participate in this consensus. This consensus consisted of 35-statements that highlighted the experts' recommendations to optimize ALL adults' care in the first line setting and manage pediatric or pediatric-inspired regimens-related toxicities. Besides, guidance was provided for future research direction and improve patient-centered communication. In conclusion, the adult-ALL management landscape is evolving, and the current evidence highlights better response and survival outcomes with pediatric or pediatric-inspired regiments. Therefore, protocols are needed to optimize the adult-ALL management in the GCC and tailored clinical-trials findings according to the GCC patients' characteristics and local-healthcare infrastructure.

The mortality of COVID-19 in CML patients from 2020 until 2022: results from the EPICOVIDEHA survey.

Since the beginning of the COVID-19 pandemic, there has been an overall improvement in patient mortality. However, haematological malignancy patients continue to experience significant impacts from COVID-19, including high rates of hospitalization, intensive care unit (ICU) admissions, and mortality. In comparison to other haematological malignancy patients, individuals with chronic myeloid leukemia (CML) generally have better prognosis. This study, conducted using a large haematological malignancy patient database (EPICOVIDEHA), demonstrated that the majority of CML patients experienced mild infections. The decline in severe and critical infections over the years can largely be attributed to the widespread administration of vaccinations and the positive response they elicited. Notably, the mortality rate among CML patients was low and exhibited a downward trend in subsequent years. Importantly, our analysis provided confirmation of the effectiveness of vaccinations in CML patients.

Langerhans Cell Hyperplasia Mimicking Langerhans Cell Histiocytosis: A Rare Complication of COVID-19 Vaccination.

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the abnormal proliferation of Langerhans cells, a type of immune cell that is normally present in the skin and various other tissues. LCH can affect people of any age but is most commonly diagnosed in children. We report a case of a patient with LCH who developed ipsilateral axillary lymphadenopathology post-COVID-19 vaccination. Lymph node biopsy showed diffuse Langerhans cell hyperplasia which mimicked LCH. Clinically and radiologically, it looked to be a reactive lymph node. The patient was kept on follow up only and after 1 year of follow up the size of lymph nodes regressed confirming to be reactive in nature rather than neoplastic. To the best of our knowledge, this is the second case of Langerhans cell hyperplasia post-COVID-19 vaccination being reported in the literature.

Concurrent coronary artery disease and immune thrombocytopenia: a systematic review.

Introduction: Coronary artery disease (CAD) management in the setting of immune thrombocytopenia (ITP) remains very challenging to clinicians as a reasonable balance between bleeding and thrombosis risks needs to be achieved, and the evidence guiding such management is scarce. Methods: We conducted a systematic review following the PRISMA guidelines to summarize the available literature on the management and outcomes of CAD coexisting with ITP. We searched PubMed and Embase for studies published in English exploring CAD and ITP management until 05 October 2022. Two independent reviewers screened and assessed the articles for inclusion. Patients' characteristics, CAD treatment modalities, ITP treatment, and complications were reported. Results: We identified 32 CAD cases, among which 18 cases were revascularized with percutaneous coronary intervention (PCI), 12 cases underwent coronary artery bypass graft surgery (CABG), and two cases were managed conservatively. More than 50% were men, with a mean age of 61 ± 13 years and a mean baseline platelet count of 52 ± 59 × 109/L. Irrespective of the revascularization modality, most patients were treated with either corticosteroids alone, intravenous immunoglobulins (IVIG) alone, or in combination. Among those who underwent PCI, two patients had bleeding events, and one patient died. Similarly, among those with CABG, one patient developed bleeding, and one patient died. Conclusion: We found that revascularization with either PCI or CABG with the concurrent use of corticosteroids and/or IVIG for ITP was feasible, with an existing non-negligible risk of bleeding and mortality.

Differential Production of Midkine and Pleiotrophin by Innate APCs upon Stimulation through Nucleic Acid-Sensing TLRs.

Midkine (MK) and pleiotrophin (PTN) belong to the same family of cytokines. They have similar sequences and functions. Both have important roles in cellular proliferation, tumors, and diseases. They regulate and are expressed by some immune cells. We have recently demonstrated MK production by some human innate antigen-presenting cells (iAPCs), i.e., monocyte-derived dendritic cells (MDDCs) and macrophages stimulated through Toll-like receptor (TLR)-4, and plasmacytoid dendritic cells (pDCs) stimulated through TLR 7. While PTN production was only documented in tissue macrophages. TLRs 3, 7, 8, and 9 are nucleic acid sensing (NAS) TLRs that detect nucleic acids from cell damage and infection and induce iAPC responses. We investigated whether NAS TLRs can induce MK and PTN production by human iAPCs, namely monocytes, macrophages, MDDCs, myeloid dendritic cells (mDCs), and pDCs. Our results demonstrated for the first time that PTN is produced by all iAPCs upon TLR triggering (p < 0.01). IAPCs produced more PTN than MK (p < 0.01). NAS TLRs and iAPCs had differential abilities to induce the production of MK, which was induced in monocytes and pDCs by all NAS TLRs (p < 0.05) and in MDDCs by TLRs 7/8 (p < 0.05). TLR4 induced a stronger MK production than NAS TLRs (p ≤ 0.05). Monocytes produced higher levels of PTN after differentiation to macrophages and MDDCs (p < 0.05). The production of MK and PTN differs among iAPCs, with a higher production of PTN and a selective induction of MK production by NAS TLR. This highlights the potentially important role of iAPCs in angiogenesis, tumors, infections, and autoimmunity through the differential production of MK and PTN upon TLR triggering.

Limited Sampling Strategy Using End of Infusion and Six-Hour Concentrations Overestimates Intravenous Busulfan Clearance Compared With Standard Six-Point Sampling in Hematopoietic Stem Cell Transplant Patients.

BACKGROUND: Therapeutic drug monitoring for busulfan (Bu) is important to improve outcomes of hematopoietic stem cell transplantation. However, standard therapeutic drug monitoring requires multiple samples and is inconvenient, labor-intensive, and costly. Accordingly, a limited sampling strategy (LSS) was evaluated, using 2-point sampling at end of infusion and at 6 hours, and the area-under-the-curve and Bu clearances (CLs) were compared with the results obtained from the standard sampling strategy (SSS) using 5-6 samples. METHOD: The analysis was based on retrospective clinical data from 202 patients receiving intravenous Bu before hematopoietic stem cell transplantation for malignant or nonmalignant conditions. Bu plasma concentrations were measured via liquid chromatography tandem-mass spectrometry, and pharmacokinetic parameters were calculated using the PKCNA package in R program. RESULT: A total of 502 doses were analyzed by applying SSS and LSS. Using the modified Bland-Altman plot, the mean percentage difference in CL between the SSS and LSS estimates of Bu 6-hourly regimen was -41% (Limits: -53% and -30%). In the once daily regimen, the mean difference in CL between the 2 strategies on the modified Bland-Altman plot was -22% (Limits: -66% and +22%). CONCLUSIONS: The Bu CL values estimated based on the BU concentration at end of infusion and at 6 hours postinfusion were significantly higher than the values obtained via the SSS.

Current Practice of Oral Care for Hematopoietic Stem Cell Transplant Patients: A Survey of the Eastern Mediterranean Blood and Marrow Transplantation Group.

INTRODUCTION: The oral cavity is one of the most common sites impacted by hematopoietic stem cell transplantation (HSCT) with acute complications including mucositis, bleeding, salivary gland dysfunction, infection, and taste alteration. These complications may result in significant morbidity and can negatively impact outcomes such as length of stay and overall costs. As such, oral care during HSCT for prevention and management of oral toxicities is a standard component of transplant protocols at all centers. The objective of this study was to evaluate the current oral care practices for patients during HSCT at different transplant centers within the Eastern Mediterranean region. MATERIAL AND METHODS: An internet-based survey was directed to 30 transplant centers in the Eastern Mediterranean region. The survey included five sections asking questions related to (1) transplant center demographics; (2) current oral care protocol used at the center and type of collaboration (if any) with a dental service; (3) use of standardized oral assessment tools and grading systems for mucositis; (4) consultations for management of oral complications; and (5) oral health needs at each center. Data are presented as averages and percentages. RESULTS: A total of 16 responses from 11 countries were collected and analyzed, indicating a response rate of 53%. Eight centers reported that a dentist was part of the HSCT team, with four reporting oral medicine specialists specifically being part of the team. Almost all centers (15/16; 93%) had an affiliated dental service to facilitate pre-HSCT dental clearance with an established dental clearance protocol at 14 centers (87%). Dental extraction was associated with the highest concern for bleeding and the need for platelet transfusion. With respect to infection risk, antibiotic prophylaxis was considered in the setting of low neutrophil counts with restorative dentistry and extraction. All centers provide daily reinforcement of oral hygiene regimen. The most frequently used mouth oral rinses included sodium bicarbonate (68%) and chlorhexidine gluconate (62%), in addition to ice chips for dry mouth (62%). The most frequently used mucositis assessment tools were the World Health Organization scale (7/16; 43%) and visual analogue scale for pain (6/16; 37%). Mucositis pain was managed with lidocaine solution (68.8%), magic mouth wash (68.8%) and/or systemic pain medications (75%). CONCLUSIONS: Scope and implementation of oral care protocols prior to and during HSCT varied between transplant centers. The lack of a universal protocol may contribute to gaps in oral healthcare needs and management for this group of patients. Further dissemination of and education around available oral care guidelines is warranted. CLINICAL RELEVANCE: Considering oral care during HSCT a standard component of transplant protocols, the current study highlights the common oral care practices for patients at centers within the Eastern Mediterranean region.

Strategic priorities for hematopoietic stem cell transplantation in the EMRO region.

The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the wealthiest countries per capita income and some of the poorest. The population structure is also unique and contrasts with western countries, with a much younger population. The region sits in the heart of the thalassemia belt. Many countries have a significant prevalence of sickle cell disease, and cancer is on the rise in the region. Therefore, the strategic priorities for the growth and development of hematopoietic stem cell transplantation (HSCT) differ from country to country based on resources, healthcare challenges, and prevalent infrastructure. Thirty-one reporting teams to the Eastern Mediterranean Blood and Marrow Transplantation Group have active HSCT programs in 12 countries; allogeneic transplants outnumber autologous transplants, and the proportion of allotransplants for non-malignant conditions is higher in the EMRO region than in Western Europe and North America. The vast majority (99%) of allotransplants are from matched related donors. Matched unrelated donors and other alternate donor transplants are underutilized. The chance of finding a matched related donor for allografts is higher, with a significant chance of finding matched donors among non-sibling related donors. Reasons for relatively lower rates of transplants compared with other countries are multifactorial. Capacity building, development of newer centers, innovative funding, and better utilization of information technology are required to make transplantation as an accessible modality to more patients. Cost-effectiveness and cost-containment, regulation, and ensuring quality will all be priorities in planning HSCT development in the region.

Patients' knowledge and awareness of safe handling of oral anticancer agents at Sultan Qaboos University Hospital in Oman.

BACKGROUND: Safe handling of oral anticancer agents is of great concern. There is a lack of clear, national guidelines on how patients can safely handle and dispose of unwanted medications. We aimed to evaluate the safe handling, storage, and disposal of oral anticancer drugs among cancer patients and caregivers at home. METHOD: This cross-sectional survey of adult cancer patients (or their adult caregivers) used a closed-ended questionnaire from May 2019 to March 2020. RESULTS: A total of 257 patients (50 ± 15 years; range: 18-93 years) were enrolled; however, only 91% (233/257) reported self-administering oral anticancer medications. Caregivers were more likely to administer oral anticancer agents for patients ≥60 years than those <40 years old (63% vs. 8%; P = 0.001). Most patients (52%; 133/257) did not wash their hands after administering the drug; 74% (164/222) of the respondents reported that their medications were kept in a bedroom cabinet, while 18% (40/222) stored their medications in a refrigerator, and 5% (12/222) in a kitchen cabinet. A total of 55% (68/124) of patients returned their excess oral chemotherapy medications to the hospitals; however, 36% (45/124) disposed of their unused oral chemotherapy drugs in a household garbage container. CONCLUSION: While two-thirds of patients stored their oral anticancer medications properly, more than half used inappropriate handling procedures. Disposal practices were inconsistent and did not adhere to the reported international guidelines.

COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA).

Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible.

Cytomegalovirus Infection Post-hematopoietic Stem Cell Transplant: Incidence, Risk Factors, and Outcome in an Omani Cohort.

Objectives: To estimate the incidence, risk factors, and outcome of cytomegalovirus (CMV) infection during the first year following hematopoietic stem cell transplant (HSCT) among Omani patients. Methods: This retrospective study included allogenic HSCT recipients between January 2006 and December 2018. We investigated the possible factors associated with CMV infection and CMV impact on one-year mortality. Results: Among 556 recipients of allogenic HSCT, 308 (55.4%) were male, the median age was 12 years, and 366 (65.8%) had benign conditions. One-year after transplants, the prevalence of CMV infection was 59.4%, and that of CMV disease was 1.8%. Multivariate analyses revealed significant relationships between CMV infection and haploidentical transplant (p = 0.006), graft versus host disease (p = 0.013), myeloablative conditioning (p = 0.001), and patient age ≥ 12 years (p < 0.001). CMV infection was associated with an increased risk of one-year mortality (p = 0.001). One-year overall mortality was 8.3%. Conclusions: The incidence of CMV infection in this Omani cohort was comparable with earlier findings, but the disease incidence and overall mortality were lower. Older age, haploidentical transplant, myeloablative conditioning, and graft versus host disease were significantly associated with a higher risk of CMV infection. In addition, CMV infection was associated with an increased risk of overall mortality in the first year post-transplant. Our findings support early initiation of preemptive therapy at low-level CMV viremia.

Impact of mutations in epigenetic modifiers in acute myeloid leukemia: A systematic review and meta-analysis.

This is a systematic review and meta-analysis evaluating the prognostic significance of epigenetic mutations on the overall survival (OS) in Acute Myeloid Leukemia (AML). We searched for studies evaluating epigenetic mutations in AML (up to November 2018) in PubMed, Trip database and Cochrane library. Hazard ratio (HR) of outcomes were extracted, and random-effects model was used to pool the results. A total of 10,002 citations were retrieved from the search strategy; 42 articles were identified for the meta-analysis (ASXL1 = 7, TET2 = 8, DNMT3A = 12, IDH =15), with fair to good-quality studies. The pooled HR was 1.88 (95% CI: 1.49-2.36) for ASXL1 mutation, 1.39 (95% CI: 1.18-1.63) for TET2 mutation, 1.35 (95% CI 1.16-1.56) for DNMT3a and 1.54 (95% CI: 1.15-2.06) for IDH mutation. However, there was a substantial heterogeneity in the DNMT3a and IDH studies. In conclusion epigenetic mutations in ASXL1, TET2, DNMT3a and IDH adversely impact OS in patients with AML albeit with considerable heterogeneity and possibly publication bias. Further studies are required to address these limitations.

Simultaneous Onset of Haematological Malignancy and COVID: An Epicovideha Survey.

Background: The outcome of patients with simultaneous diagnosis of haematological malignancies (HM) and COVID-19 is unknown and there are no specific treatment guidelines. Methods: We describe the clinical features and outcome of a cohort of 450 patients with simultaneous diagnosis of HM and COVID-19 registered in the EPICOVIDEHA registry between March 2020 to February 2022. Results: Acute leukaemia and lymphoma were the most frequent HM (35.8% and 35.1%, respectively). Overall, 343 (76.2%) patients received treatment for HM, which was delayed for longer than one month since diagnosis in 57 (16.6%). An overall response rate was observed in 140 (40.8%) patients after the first line of treatment. After a median follow-up of 35 days, overall mortality was 177/450 (39.3%); 30-day mortality was significantly higher in patients not receiving HM treatment (42.1%) than in those receiving treatment (27.4%, p = 0.004), either before and/or after COVID-19, or compared to patients receiving HM treatment at least after COVID-19 (15.2%, p < 0.001). Age, severe/critical COVID-19, ≥2 comorbidities, and lack of HM treatment were independent risk factors for mortality, whereas a lymphocyte count >500/mcl at COVID-19 onset was protective. Conclusions: HM treatment should be delivered as soon as possible for patients with simultaneous diagnosis of COVID-19 and HM requiring immediate therapy.

Human macrophages and monocyte-derived dendritic cells stimulate the proliferation of endothelial cells through midkine production.

The cytokine midkine (MK) is a growth factor that is involved in different physiological processes including tissue repair, inflammation, the development of different types of cancer and the proliferation of endothelial cells. The production of MK by primary human macrophages and monocyte-derived dendritic cells (MDDCs) was never described. We investigated whether MK is produced by primary human monocytes, macrophages and MDDCs and the capacity of macrophages and MDDCs to modulate the proliferation of endothelial cells through MK production. The TLR stimulation of human monocytes, macrophages and MDDCs induced an average of ≈200-fold increase in MK mRNA and the production of an average of 78.2, 62, 179 pg/ml MK by monocytes, macrophages and MDDCs respectively (p < 0.05). MK production was supported by its detection in CD11c+ cells, CLEC4C+ cells and CD68+ cells in biopsies of human tonsils showing reactive lymphoid follicular hyperplasia. JSH-23, which selectively inhibits NF-κB activity, decreased the TLR-induced production of MK in PMBCs, macrophages and MDDCs compared to the control (p < 0.05). The inhibition of MK production by macrophages and MDDCs using anti-MK siRNA decreased the capacity of their supernatants to stimulate the proliferation of endothelial cells (p = 0.01 and 0.04 respectively). This is the first study demonstrating that the cytokine MK is produced by primary human macrophages and MDDCs upon TLR triggering, and that these cells can stimulate endothelial cell proliferation through MK production. Our results also suggest that NF-κB plays a potential role in the production of MK in macrophages and MDDCs upon TLR stimulation. The production of MK by macrophages and MDDCs and the fact that these cells can enhance the proliferation of endothelial cells by producing MK are novel immunological phenomena that have potentially important therapeutic implications.

Impact of Glutathione S-Transferase Polymorphisms on Busulfan Pharmacokinetics and Outcomes of Hematopoietic Stem Cell Transplantation.

BACKGROUND: Busulfan (Bu) is an alkylating drug used in many preparative regimens before hematopoietic stem cell transplantation (HSCT). It is conjugated in the liver mainly by glutathione S-transferase isoenzyme A1-1 ( GSTA1 ). Genetic polymorphisms in these isoenzymes may affect the pharmacokinetics of Bu and the clinical outcomes of HSCT. This study aimed to assess the impact of glutathione S-transferase ( GST ) genetic polymorphisms on the clearance of Bu and the clinical outcomes of patients undergoing HSCT. METHODS: This single-center retrospective study included patients who received IV Bu before HSCT at Sultan Qaboos University Hospital (SQUH), Oman from January 2003 to October 2016. Genotyping for polymorphisms was performed for GSTM1 , GSTT1 , GSTA1 , and GSTP1 . Each GST polymorphism was analyzed for its impact on Bu clearance and HSCT outcomes. RESULTS: A total of 135 patients were included. The mean Bu clearance was 3.7 ± 0.98 mL/min/kg. Patients with GSTA1 A-513G heterozygosity (AG) were found to have a higher incidence of graft loss ( P = 0.006). Homozygous double null of GSTM1 and GSTT1 was associated with a higher incidence of acute graft versus host disease ( P = 0.04). Double non-null GSTM1 and GSTT1 and non-null GSTM1 increased the risk of mortality ( P = 0.034 and 0.021, respectively). CONCLUSIONS: GST genotyping before HSCT may predict HSCT outcomes. The results of this preliminary retrospective study need to be confirmed in a larger prospective study.