Prognostic impact of chronic lymphocytic leukemia comorbidity index in a young population: a real-world evidence study of a national gulf region cohort.

In chronic lymphocytic leukaemia (CLL), comorbidities assessed by the CLL comorbidity index (CLL-CI) have been associated with outcomes in Western cohorts. We conducted a retrospective analysis of an unselected Middle Eastern cohort of newly diagnosed CLL patients seen at the Kuwait Cancer Control Center (n = 300). Compared to Western studies, these Middle Eastern patients were diagnosed at a younger age (median of 59) and had a higher comorbidity burden (69% non-low risk CLL-CI). A higher CLL-CI score was independently associated with significantly shorter event-free survival and greater risk of death. Our analysis demonstrates that CLL-CI is a valuable tool for comorbidity assessment and prognostic influence in (relatively young) Middle Eastern CLL patients.

Predicting Stage Progression in Binet Stage a Chronic Lymphocytic Leukemia.

INTRODUCTION: The variable clinical course of chronic lymphocytic leukemia (CLL) and the lack of consensus on follow-up and treatment strategies have necessitated a prognostic model for identifying high-risk patients at the time of diagnosis. METHODS: We involved a retrospective analysis of demographic and clinical characteristics of 212 patients diagnosed with Binet stage A CLL and thus eligible for risk stratification by both the International Prognostic Score for Early-stage CLL (IPS-E) and the alternative IPS-E (AIPS-E). We evaluated the applicability of these prognostic indices in our young, Middle Eastern cohort (median age 59 at diagnosis). RESULTS: During the study period with a median follow-up of 3.5 years, 67 patients (32 %) experienced progression to first treatment and cumulative incidence of treatment was 13 % at 1 year and 28 % at 3 years after diagnosis. Sixty-nine (51 % of the 136 with a known value) patients harbored an unmutated immunoglobulin heavy chain gene (IGHV) and 21 (10 %) an 11q or 17p deletion with 11 % lacking FISH results. For each early-stage CLL prognostic index, more patients were identified as high-risk for disease progression (51 % of 124 patients evaluable for IPS-E; 42 % of 109 patients evaluable for AIPS-E) than intermediate-risk and low-risk. Multivariable models involving the IPS-E and AIPS-E components revealed that unmutated IGHV and elevated absolute lymphocyte count were significant predictors of earlier treatment requirement. Both prognostic scores were discriminative of time to first treatment (log-rank p < 0.001; c-statistics of 0.74 for IPS-E and 0.69 for AIPS-E). CONCLUSION: Although clarity on clinical behavior with regard to initiation of treatment remains elusive, IPS-E and AIPS-E are valuable tools for identifying high-risk patients.

Evidence-based Management of Chronic Lymphocytic Leukemia: Consensus Statements from the Gulf Region.

INTRODUCTION: Despite recent advances in diagnosis, prognostication, and treatment options, chronic lymphocytic leukemia (CLL) is still a largely incurable disease. New concepts on diagnosis, staging, treatment, and follow-up on CLL have been incorporated throughout recent years. The lack of regional consensus guidelines has led to varying practices in the management of patients with CLL in the region. AIM: This manuscript aims to reach a consensus among expert hematologists regarding the definitions, classifications, and related practices of CLL. The experts developed a set of statements utilizing their personal experience together with the current literature on CLL management. This consensus aims to provide guidance for healthcare professionals involved in the management of CLL and serves as a step in developing regional guidelines. METHODS: Eight experts responded to 50 statements regarding the diagnosis, staging, treatment, and prognosis of CLL with three potential answering alternatives ranging between agree, disagree, and abstain. This consensus adopted a modified Delphi consensus methodology. A consensus was reached when at least 75% of the agreement to the answer were reached. This manuscript presents the scientific insights of the participating attendees, panel discussions, and the supporting literature review. RESULTS: Of the 50 statements, a consensus was reached on almost all statements. Statements covered CLL-related topics, including diagnostic evaluation, staging, risk assessment, different patient profiles, prognostic evaluation, treatment decision, therapy sequences, response evaluation, complications, and CLL during the COVID-19 pandemic. DISCUSSION/CONCLUSION: In recent years, CLL management has progressed significantly with many diagnostic tests and several novel treatments becoming available. This consensus gathers decades of consolidated principles, novel research, and promising prospects for the management of this disease.

Evaluation of the CLL-IPI and IPS-E Prognostic Indices in a Young Middle Eastern Population with Chronic Lymphocytic Leukemia: A Retrospective Analysis at the Kuwait Cancer Control Center.

INTRODUCTION: The Chronic Lymphocytic Leukemia International Prognostic Index (CLL-IPI) is a powerful prognostic tool validated in multiple Western populations. However, its utility in the young Middle Eastern population is unknown. METHODOLOGY: We conducted a retrospective analysis of 152 unselected patients with chronic lymphocytic leukemia (CLL) diagnosed between 2008 and 2022 at the Kuwait Cancer Control Center, which serves as the sole cancer center in Kuwait. The evaluation of the CLL-IPI was based on the assessment of event-free survival (EFS) across the entire cohort. Subsequently, we compared the CLL-IPI with the International Prognostic Score for Early-stage patients (IPS-E) in order to predict the time to first treatment specifically within the subgroup of patients diagnosed with early-stage disease. RESULTS: The median age of the study cohort was 59.9 years (IQR, 53.1-68.8). The 5-year EFS rates for the low, intermediate, and high/very high-risk categories were approximately 82%, 34%, and 23%, respectively, p < 0.001 (C-statistic = 0.67). On multivariate analysis, advanced stage and unmated IGHV status were independent prognostic factors of EFS. In those with early-stage disease, cumulative 5-year treatment incidence rates for the low, intermediate, and high/very high-risk categories based on the CLL-IPI score were approximately 8%, 55%, and 55%, respectively, p = 0.001 (C-statistic = 0.70). However, based on the IPS-E score, the cumulative 5-year treatment incidence rates for the low, intermediate, and high-risk categories were approximately 0%, 10%, and 60%, respectively, p < 0.001 (C-statistic = 0.73). CONCLUSIONS: The CLL-IPI and the IPS-E are valid stratification tool in our young Middle Eastern population.

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.

FIP1L1-PDGFRA fusion gene in T-lymphoblastic lymphoma: A case report.

BACKGROUND: T-lymphoblastic lymphoma (T-LBL) is an aggressive malignancy of T-lymphoid precursors, rarely co-occurring with myeloid/lymphoid neoplasms with eosinophilia (M/LNs-Eo), with consequent rearrangement of tyrosine kinase (TK)-related genes. The FIP1L1-PDGFRA fusion gene is the most frequent molecular abnormality seen in eosinophilia-associated myeloproliferative disorders, but is also present in acute myeloid leukemia (AML), T-lymphoblastic leukemia/lymphoma (TLL), or both simultaneously. T-LBL mainly affects children and young adults, involving lymph node, bone marrow, and thymus. It represents about 85% of all immature lymphoblastic lymphomas, whereas immature B-cell lymphomas comprise approximately 15% of all cases of LBL. CASE: In this case report, we present an example of T cell lymphoblastic lymphoma with coexistent eosinophelia, treated successfully with a tyrosine-kinase inhibitor (TKI). CONCLUSION: FIP1L1-PDGFRA-positive T-LBL and myeloproliferative disorders have excellent response to low-dose treatment with (TKI) imatinib. Most patients achieve rapid and complete hematologic and molecular remission within weeks.

Fatal COVID-19 is Associated with Reduced HLA-DR, CD123 or CD11c Expression on Circulating Dendritic Cells.

Purpose: Severe coronavirus disease 2019 (COVID-19) is linked to insufficient control of viral replication and excessive inflammation driven by an unbalanced immune response. Plasmacytoid dendritic cells (pDCs) are specialized in the rapid production of interferons in response to viral infections, and can also prime and activate T-cells. Conventional DCs (cDCs) are critical for the elimination of viral infections owing to their specialized ability to prime and activate T cells. We assessed the frequency and phenotype of pDCs and cDCs in survivors and non-survivors of COVID-19. Patients and methods: Patients with COVID-19 were enrolled, and 22 were included in this study. Peripheral whole blood was obtained during the 2nd week of illness, stained with antibodies specific for lineage markers, human leukocyte antigen-DR isotype (HLA-DR), CD11c, and CD123, and analyzed by flow cytometry. Patients were followed-up during hospital admission and grouped into survivors (n=17) and non-survivors (n=5) of COVID-19. Results: The ratio of pDCs to pre-cDCs was significantly lower (P=0.0005) in non-survivors compared to survivors. The frequency of pDCs was significantly higher than cDC2-like cells (P=0.0002) and pre-cDCs (P<0.0001) in survivors but not in non-survivors. HLA-DR expression level on pDCs and cDC2-like cells was lower in non-survivors compared to survivors (P=0.02 and P=0.058, respectively), and HLA-DR was inversely correlated with disease severity rating (pDCs: r= -0.47, P=0.027; cDC2-like cells: r= -0.45, P=0.037). CD123 expression level on pDCs was significantly lower (P=0.038) in non-survivors compared to survivors, and CD123 was inversely correlated with disease severity rating (r=-0.5, P=0.016). CD11c expression level on cDC2-like cells was significantly lower (P=0.03) in non-survivors compared to survivors, and CD11c was inversely correlated with disease severity rating (r=-0.47, P=0.025). Conclusion: A lower frequency of pDCs compared to other circulating DCs, and lower expression levels of HLA-DR, CD123 or CD11c on DCs is associated with fatal COVID-19.

Epidemiology of de novo Acute Myeloid Leukemia in Kuwait per the 2016 WHO Classification.

OBJECTIVE: Acute myeloid leukemia (AML) is a hematological malignancy that arises from the clonal proliferation of immature myeloid cells. Although the number of AML cases has dramatically increased worldwide, information on its prevalence and incidence in Kuwait is lacking. This study reports the incidence of AML and patient demographics in the country from 2014 to 2020, based on the 2016 WHO classification of AML. SUBJECTS AND METHODS: Data on patients with AML, including acute promyelocytic leukemia (APL), were collected from a clinical cohort with 281 cases analyzed in this study. RESULTS: The overall median age of the population was 47 years with a 1.1:1 male-to-female ratio. Over the study period, the incidence of AML demonstrated a general increasing trend, with the highest and lowest overall incidence occurring in 2018 and 2015, respectively. The frequency of APL in our cohort was 8.9%. Regarding the 2017 European LeukemiaNet (ELN) risk stratification of patients with AML, 37%, 46%, and 17% of patients had a favorable, intermediate, and adverse risk, respectively. A total of 57% of cases achieved complete remission post-induction, and the median overall survival was 37 months. CONCLUSION: Our study may help predict the future trends of AML in Kuwait to help improve clinical management and patient outcomes.

Primary Mediastinal Large B-cell Lymphoma : Impact of Chemotherapy Choice.

OBJECTIVE/BACKGROUND: Data generated from retrospective studies on primary mediastinal B-cell lymphoma (PMBCL) outcome are valuable as no prospective phase 3 trials have been conducted in this rare type of lymphoma. METHODS: Our goal was to assess the long-term outcome of 41 patients with PMBCL who were treated at the Kuwait Cancer Center. We evaluated two types of multidrug treatment, R-CHOP (rituximab, vincristine, doxorubicin, cyclophosphamide, and prednisone) and DA-EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), and determined overall survival and complete response (CR) as primary endpoints. RESULTS: In our cohort, 27 (66%) cases were treated with R-CHOP and 14 (34%) cases were treated with DA-EPOCH-R. The overall median follow-up time was 34 months. Among the patients treated with R-CHOP, 23 out of 27 (92.6%) patients achieved CR; similarly, 10 out of 14 patients (85.7%) in the DA-EPOCH-R group achieved CR after initial treatment. There were no differences in OS between patients treated with R-CHOP versus DA-EPOCH-R. CONCLUSION: The findings of this study indicate that combined chemotherapy and immunotherapy results in excellent long-term outcome of patients with PMBCL. At our center, we prefer R-CHOP to DA-EPOCH-R for low-risk patients with nonbulky disease.

Chronic lymphocytic leukemia in a young population.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is uncommon in the Middle East. There is limited data on the prognosis and of CLL in this region. METHODS: This was a retrospective study (2009-2020) of consecutively diagnosed patients with CLL at Kuwait Cancer Center. The diagnosis, prognosis, treatment indication, response criteria, and adverse events were recorded per International Workshop on Chronic Lymphocytic Leukemia guidelines. RESULTS: A total of 219 patients with CLL were enrolled in the study. The crude annual incidence is 0.4 per 100,000. The median follow-up was 120 months. The median age at diagnosis was 59 years, and 32 % of patients with CLL were ≤ 55 years of age. Prognostic fluorescence in situ hybridization data were available in 213 cases. del (13q14/13q34) was found in 80 (31 %) cases, del (11q) in 23 (10.7 %) cases, del (17p) in 11 (5.16 %) cases, and trisomy 12 in 46 (21.5 %) cases. IGHV mutation status was available in 92 cases, 45 of which (48.9) were mutated and 47 (51.1 %) of which were not. The median progression-free survival (PFS) for the entire cohort was 178 months [95 % CI: 145-NE].· The median OS was 203 months [95 % CI: 145-NE]. The median PFS for the IGHV mutated cases was not reached [95 % CI: 178 - NE]; while the median PFS for the unmutated CLL cases was 24 months [95 % CI: 124 - NE]. CONCLUSION: CLL is a rare hematological malignancy in the Middle East. Our CLL cohort is younger and expresses less del13q, but has similar rates of IGHV mutations.

Prognosis and Outcome of Fit Patients with Acute Myeloid Leukemia in Kuwait.

PURPOSE: Acute myeloid leukemia (AML) data from the Middle East are limited to single-center studies. We report leukemia-free survival (LFS) and overall survival (OS) of young (≤70 years) patients with AML treated in Kuwait. PATIENTS AND METHODS: This study investigated prognostic markers among 172 young and fit patients with de novo nonacute promyelocytic leukemia AML treated with intensive induction protocols from a tertiary cancer center. RESULTS: The median age was 44 years (interquartile range, 32-51) and 67% of cases were Arab. A greater proportion of males was found in the 2017 European Leukemia Net-defined unfavorable-risk group (20% vs 9%, respectively; P = .02). Most patients (94%) were treated by a standard 7 × 3 regimen; 72.5% of cases achieved complete remission. The 24-month LFS was 44% (95% confidence interval, 30-65), 36% (95% confidence interval, 26-50), and 23% (95% confidence interval, 10-53) for the favorable-, intermediate-, and adverse-risk groups, respectively (P = .018). The 24-month OS was 70% (95% confidence interval, 60-90), 65% (95% confidence interval, 53-79), and 49% (95% confidence interval, 31-78), respectively (P = .05). Multivariable factor analysis identified male gender (hazard ratio [HR], 1.66; P = .029) and older age (HR, 1.02; P = .05) with poor LFS outcome, whereas favorable-risk classification predicated better outcome (HR, 0.49; P = .03). Favorable-risk classification was the only predictor of OS (HR, 0.39; P = .029). CONCLUSION: Fit patients with AML in the favorable-risk group treated with intensive chemotherapy fare well, whereas patients in the adverse-risk group have poor survival.

Special issues related to the diagnosis and management of acquired aplastic anemia in countries with restricted resources, a report on behalf of the Eastern Mediterranean blood and marrow transplantation (EMBMT) group and severe aplastic anemia working party of the European Society for blood and marrow transplantation (SAAWP of EBMT).

Aplastic anemia is a relatively rare but potentially fatal disorder, with a reported higher incidence in developing countries in comparison to the West. There are significant variations in epidemiological as well as etiological factors of bone marrow failure syndromes in the developing countries in comparison to the developed world. Furthermore, the management of bone marrow failure syndromes in resource constraint settings has significant challenges including delayed diagnosis and referral, limited accessibility to healthcare facilities, treatment modalities as well as limitations related to patients who require allogeneic stem cell transplantation. Here we will provide a review of the available evidence related to specific issues of aplastic anemia in the developing countries and we summarize suggested recommendations from the Eastern Mediterranean blood and bone marrow transplantation (EMBMT) group and the severe aplastic anemia working party of the European Society of blood and marrow transplantation (SAAWP of EBMT) related to the diagnosis and therapeutic options in countries with restricted resources.

Association analysis of genetic variants in the ghrelin and tumor necrosis factor α genes and the risk for non-Hodgkin's lymphoma in Kuwaitis.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy in the world. Many etiologic factors have been implicated in the risk of developing NHL, including genetic susceptibility and obesity. Single-nucleotide polymorphisms (SNPs) in Ghrelin (GHRL), an anti-inflammatory hormone, and tumor necrosis factor α (TNF-α), an inflammatory cytokine, have been independently associated with the risk for obesity and NHL. OBJECTIVE: To investigate the association between SNPs in GHRL and TNF-α and the risk for NHL and obesity in Kuwaitis. METHODS: We recruited 154 Kuwaiti NHL patients and 217 controls. Genotyping was performed for rs1629816 (GHRL promoter region), rs35684 (GHRL 3' untranslated region), and rs1800629 (TNF-α promoter region). Logistic regression analysis was performed to assess the association of the investigated SNPs with NHL and the relationship between the selected SNPs with BMI in each group separately. RESULTS: We show that rs1629816 GG was associated with an increased risk for NHL in our sample (p= 0.0003, OR 1.82; CI: 1.31-2.54). None of the investigated SNPs were associated with obesity, nor was obesity found to be associated with the risk for NHL. CONCLUSIONS: Our study demonstrates an association between rs1629816, a SNP in the GHRL regulatory region, and NHL in Kuwaitis.

Analysis of Common Driver Mutations in Philadelphia-Negative Myeloproliferative Neoplasms.

BACKGROUND: Philadelphia-negative myeloproliferative neoplasms (MPNs) are a group of hematopoietic stem cell disorders that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). This study examines the driver mutations among patients with MPNs in Kuwait. PATIENTS AND METHODS: This study was a retrospective review of 942 MPN cases with a driver mutation from July 2007 to June 2019 to examine their demographic, clinical, and laboratory attributes. RESULTS: The annual incidence of MPNs is 1.6 per 100,000 persons, and ET is the most common subtype. The median age of our cohort was 55 years, and the patients were predominantly male. We found that the most frequent gene mutation of MPNs in our cohort was the JAK2V617F mutation, which was present in 90% of cases, followed by the CALR exon 9, MPLW515L/K, and JAK2 exon 12 mutations. In our cohort, thrombotic events were observed in 18.7% of cases. CONCLUSION: Although Philadelphia-negative MPNs are rare hematologic malignancies, thrombosis is a relatively common initial presentation. The JAK2V617F mutation was the driver mutation in the majority of patients with MPN.

Philadelphia-negative myeloproliferative neoplasms among Kuwaiti Nationals.

The epidemiology, genetics, and thrombosis risk of MPNs among Arabs are largely unknown. This may be attributed to scarce epidemiological data, particularly from our region. Our study included 381 Kuwaiti nationals with Ph-negative MPNs and a confirmed driver mutation involving JAK2 (exon 12 14), CALR, or MPL. This first regional study examines the demographics, clinical parameters, and thrombosis-related attributes of the participants. This study reported a median age of 58 years, with females and males representing 54.9% and 45.1%, respectively. ET was the most frequent subtype of Ph-negative MPNs in our population, accounting for 52.0% of the cases, followed by PV, found in 34.6% of the participants, and PMF, found in 8.4% of participants. The crude annual cumulative incidence of Ph-negative MPNs in Kuwait ranged from 0.674 to 3.177 per 100,000 population across the study period. The most common driver mutation was JAK2V617F, with a frequency of 89.5%. At diagnosis, 19.2% of the patients presented with unexplained thrombosis, and almost half were of arterial origins. Males were more likely to present with arterial thrombosis than females (61.5% vs. 35.3%), whereas venous thrombotic events were more common in females than in males (47.1% vs. 17.9%; p-value = 0.025). Ph-negative MPNs in Kuwait are rare; however, thrombosis is a frequent complication, being documented in up to 19.2% of cases at presentation, more commonly at arterial sites. These findings call for thorough evaluation of patients with unexplained derangements in their hematological parameters during follow-ups.

Promising effect of PDL1 inhibitors in the front-line management of primary aggressive central nervous system lymphoma: A case report.

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma that involves the central nervous system. The standard treatment involves chemotherapy with high-dose methotrexate. To the best of our knowledge, this is the first reported case of employing checkpoint inhibitor, nivolumab, alone to treat a patient with PCNSL who could not tolerate the induction therapy. In aggressive cases of PCNSL where chemotherapy may become futile, stand-alone checkpoint inhibitors should be considered as the front-line treatment protocol.

UPLC-Tandem Mass Spectrometry for Quantification of Busulfan in Human Plasma: Application to Therapeutic Drug Monitoring.

Busulfan (Bu) is an alkylating agent commonly used in preparative regimens for hematologic malignant and non-malignant patients undergoing hematopoietic stem cell transplantation (HSCT). The objective of the present study was to develop an UPLC-MS/MS method for quantification of Bu in human plasma. A total of 55 patients with hematologic malignancies (n = 34) and non- malignancies (n = 21) received myeloablative Bu therapy prior to HSCT. A tandem mass spectrometric method was developed and validated to quantify Bu levels in these patients. The method was fully validated over the concentration range of 25-2000 ng/mL (r > 0.99). The assay method demonstrated good precision and accuracy. Stability studies indicated that the drug was stable in various conditions. Incurred sample reanalysis findings were within acceptable ranges (<15% of the nominal concentration). Based on the 1st dose AUC results, one third of hematologic malignant patients and half of non-malignant patients needed dose adjustment. However, in subsequent doses (5th, 9th, and 13th), 77%, 82% and 82%, respectively, of hematologic malignant patients and 71%, 67% and 86%, respectively, of non-malignant patients achieved the target range of Bu AUC. The suitability of the developed method for routine TDM of Bu in HSCT patients was demonstrated. The study suggests that the pharmacokinetic profile of Bu varies in both groups.

Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review.

Primary myelofibrosis (PMF) is a rare chronic BCR-ABL1-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of PMF include splenomegaly, consequent to extramedullary hematopoiesis, pancytopenias, and an array of potentially debilitating constitutional symptoms. The diagnosis is based on bone marrow morphology and clinical criteria. Mutations in the JAK2 (V617F), MPL (W515), and CALR (exon 9 indel) genes are found in approximately 90% of patients whereas the remaining 10% are so-called triple negatives. Activation of the JAK/STAT pathway results in overproduction of abnormal megakaryocytes leading to bone marrow fibrosis. These mutations might be accompanied by other mutations, such as ASXL1. The commonly used prognostication scoring for PMF is based on the International Prognostic Scoring System. The subsequently developed Dynamic International Prognostic Scoring System-plus employs clinical as well as cytogenetic variables. In PMF, CALR mutation is associated with superior survival and ASXL1 with inferior outcome. Patients with triple-negative PMF have a higher incidence of leukemic transformation and lower overall survival compared with CALR- or JAK2-mutant patients. The impact of genetic lesions on survival is independent of current prognostic scoring systems. These observations indicate that driver and passenger mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

Association of Genetic Polymorphisms in the VKORC1 and CYP2C9 Genes with Warfarin Dosage in a Group of Kuwaiti Individuals.

BACKGROUND AND OBJECTIVE: Warfarin is the most widely prescribed oral anticoagulant worldwide. The narrow therapeutic index and the large variation in the inter-individual dose of warfarin are problematic, since the side effects can be lethal. Single nucleotide polymorphisms (SNP) in CYP2C9 and VKORC1 have been shown to significantly affect warfarin dosage toleration and this effect varies among different populations. We aimed to investigate the effect of these SNPs on warfarin dosage in a sample of Kuwaiti patients. METHODS: Kuwaiti patients who were taking a maintenance dose of warfarin were genotyped for CYP2C9*1, *2 and *3 and VKORC1 rs9923231, rs9934438, rs7294 and rs2884737. The association of these SNPs with the warfarin dose was evaluated. RESULTS: For CYP2C9, the CYP2C9 *1/*1 genotype required a higher dose (5.5 ± 3.3 mg/day) compared to non-*1/*1 (3.3 ± 1.7 mg/day) (p = 0.003). For VKORC1, the daily warfarin dose was significantly different (p = 0.001) among the three genotypes of rs9923231, rs9934438 and rs2884737, with carriers of the wild-type genotype requiring the highest dose compared to variant allele carriers (p ≤ 0.001-0.002). There was no association found between the daily warfarin dose and the rs7294 polymorphism. CONCLUSIONS: Our data showed that individuals carrying the wild-type allele of CYP2C9 or VKORC1 rs9923231, rs9934438 or rs2884737 are less sensitive than individuals with the variant alleles of these SNPs and therefore required a higher daily maintenance dose of warfarin. Our study confirms the association between SNPs in CYP2C9 and VKORC1 and warfarin dose tolerance in Kuwaiti patients.