Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy.

BACKGROUND: Although hypomethylating agents are currently used to treat patients with cancer, whether they can also reactivate and up-regulate oncogenes is not well elucidated. METHODS: We examined the effect of hypomethylating agents on SALL4, a known oncogene that plays an important role in myelodysplastic syndrome and other cancers. Paired bone marrow samples that were obtained from two cohorts of patients with myelodysplastic syndrome before and after treatment with a hypomethylating agent were used to explore the relationships among changes in SALL4 expression, treatment response, and clinical outcome. Leukemic cell lines with low or undetectable SALL4 expression were used to study the relationship between SALL4 methylation and expression. A locus-specific demethylation technology, CRISPR-DNMT1-interacting RNA (CRISPR-DiR), was used to identify the CpG island that is critical for SALL4 expression. RESULTS: SALL4 up-regulation after treatment with hypomethylating agents was observed in 10 of 25 patients (40%) in cohort 1 and in 13 of 43 patients (30%) in cohort 2 and was associated with a worse outcome. Using CRISPR-DiR, we discovered that demethylation of a CpG island within the 5' untranslated region was critical for SALL4 expression. In cell lines and patients, we confirmed that treatment with a hypomethylating agent led to demethylation of the same CpG region and up-regulation of SALL4 expression. CONCLUSIONS: By combining analysis of patient samples with CRISPR-DiR technology, we found that demethylation and up-regulation of an oncogene after treatment with a hypomethylating agent can indeed occur and should be further studied. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).

Comparing transfusion reactions between pre-storage and post-storage leukoreduced apheresis platelets: an analysis using propensity score matching.

Transfusion reactions induced by platelet transfusions may be reduced and alleviated by leukocyte reduction of platelets. Although leukoreduction of apheresis platelets can be performed either pre-storage or post-storage, seldom studies directly compare the incidence of transfusion reaction in these two different blood products. We conducted a retrospective study to compare the transfusion reactions between pre-storage and post-storage leukoreduced apheresis platelets. We reviewed the general characteristics and the transfusion reactions, symptoms, and categories for inpatients who received pre-storage or post-storage leukoreduced apheresis platelets. Propensity-score matching was performed to adjust for baseline differences between groups. A total of 40,837 leukoreduction apheresis platelet orders were reviewed. 116 (0.53%) transfusion reactions were reported in 21,884 transfusions with pre-storage leukoreduction, and 174 (0.91%) reactions were reported in 18,953 transfusions with post-storage leukoreduction. Before propensity-score matching, the odds ratio for transfusion reactions in the pre-storage group relative to the post-storage group was 0.57 (95% confidence interval [CI] 0.45-0.72, P < 0.01); the odds ratio after matching was 0.63 (95% CI 0.49-0.80, P < 0.01). A two-proportion z-test revealed pre-storage leukoreduction significantly decreases the symptoms of chills, fever, itching, urticaria, dyspnea, and hypertension as compared with those in post-storage leukoreduction. Pre-storage leukoreduced apheresis platelet significantly decreased febrile non-hemolytic transfusion reaction as compared with post-storage groups. This study suggests pre-storage leukoreduction apheresis platelet significantly decreases the transfusion reaction as compared with those in post-storage leukoreduction.

Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

Prognostic factors in patients with bone marrow hemophagocytosis and its association with hematologic malignancies.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of hyperinflammatory statuses that are difficult to diagnose and can be life-threatening. Bone marrow (BM) hemophagocytosis is one of the diagnostic criteria according to HLH 2004 diagnostic criteria and HS score. Limited studies have focused on the prognostic factors of BM hemophagocytosis and its association with hematologic malignancies. We aimed to analyze the clinical significance of BM hemophagocytosis. Patients with BM hemophagocytosis, either by cytology or pathology, were enrolled at Taipei Veterans General Hospital from January 2002 to July 2021. Relevant clinical and laboratory data were extracted from medical records. Of 119 patients with BM hemophagocytosis, 57 were diagnosed with hematologic malignancies. The median age of the patients was 58, ranging from 21 to 90. Splenomegaly (adjusted odds ratio [aOR] 2.96; 95% confidence interval [CI] 1.13-7.79) was a risk factor for hematologic malignancies, while autoimmune disease (aOR 0.07; 95% CI 0.01-0.39) and increased D-dimer (aOR 0.25; 95% CI 0.07-0.92) were protective factors. Risk factors for mortality in patients with BM hemophagocytosis were hematologic malignancies (adjusted hazard ratio [aHR] 2.34; 95% CI 1.24-4.44), Eastern Cooperative Oncology Group score ≥3 (aHR 2.42; 95% CI 1.20-4.89) and thrombocytopenia (aHR 3.09; 95% CI 1.04-9.16). In conclusion, among patients with BM hemophagocytosis, splenomegaly was a predictor of hematologic malignancies. Patients with hematologic malignancies, poor performance status, or thrombocytopenia had a higher mortality risk. Further validation studies are warranted.

Risk Factors and Outcomes of Stem Cell Mobilization Failure in Multiple Myeloma Patients.

Introduction: Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment for patients with multiple myeloma (MM), and adequate stem cell collection must be assured before ASCT. However, prediction of poor mobilizers (PMs) is still difficult despite several risk factors for mobilization failure having been identified. Methods: We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan who underwent stem cell collection between October 2006 and August 2020. A CD34+ cell collection of <1 × 106 cells/kg was defined as a mobilization failure. The primary endpoint was mobilization failure. The secondary endpoint was overall survival (OS). Odds ratios (ORs) and 95% confidence intervals (CIs) for mobilization failure were calculated using a logistic regression model. The cumulative incidence of mortality was estimated using the Kaplan-Meier method. Results: In the multivariate analysis, absolute monocyte count <500/µL (adjusted OR 10.75, 95% CI: 1.82-63.57, p = 0.009), platelet count <150,000/µL (adjusted OR 12.49, 95% CI: 2.65-58.89, p = 0.001) before mobilization, and time interval from diagnosis to stem cell harvest ≥180 days (adjusted OR 7.69, 95% CI: 1.61-36.87, p = 0.011) were risk factors for PMs. PM patients had poorer OS compared to patients with successful stem cell collection in the univariate analysis (log-rank test p = 0.027). The predicted probability of PMs was estimated by the multiple logistic regression model with a sensitivity of 84.6% and a specificity of 84.0%. Conclusion: Absolute monocyte count <500/µL, platelet count <150,000/µL, and treatment duration more than 180 days before stem cell mobilization are risk factors for unsuccessful stem cell collection. Our prediction models have high sensitivity and specificity for mobilization failure prediction and allow for early interventions for possible PMs.

Underweight as a risk factor of mortality in patients with newly diagnosed multiple myeloma.

PURPOSE: Multiple myeloma (MM), a clonal plasma cell malignancy, composes around 10% of hematologic malignancies. Though recent advances in treatment have dramatically improved MM survival, some aggressive courses of disease and dismal outcomes still exist. Low body weight, undernutrition, and cachexia are noted at MM diagnosis. We aim to evaluate the impact of low body mass index (BMI) and undernutrition in MM patients. METHODS: We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 1, 2006 and October 31, 2018. Being underweight is defined as having a BMI of under 18.5 kg/m2. The patient's baseline characteristics, including BMI, serum albumin level, and comorbidities, etc., were recorded. The primary endpoint of the study was all-cause mortality. A Cox regression model was used to estimate the risk factors of mortality. RESULTS: A total of 378 newly diagnosed MM patients were enrolled in this study. The median age of the patients was 69. Thirty patients (7.9%) were underweight at diagnosis. The median overall survival was 1.3 years (95% CI 0.3-5.7) and 5.0 years (95% CI 3.1-5.9) for patients with low BMI and for patients with normal or higher BMI, respectively. In the multivariate analysis, low BMI (95% CI 1.07-4.44), ECOG ≥2 (95% CI 1.02-2.89), hypoalbuminemia (95% CI 1.21-4.01), high LDH (95% CI 1.22-3.49), and light chain ratio > 100 (95% CI 1.06-2.77) were independent risk factors of mortality. CONCLUSION: MM patients who were underweight, with hypoalbuminemia, poor performance status, higher LDH, and light chain ratio > 100 were associated with poor overall survival.

Risk and impact of invasive fungal infections in patients with multiple myeloma.

Infection is associated with great morbidity and mortality in patients with multiple myeloma (MM), but evidence for invasive fungal infections (IFIs) is lacking. We aimed to investigate risk factors for IFI in MM patients and to determine its impact on patients' survival. We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 2002 and October 2018. MM was diagnosed according to the International Myeloma Working Group criteria. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. All risk factors of IFI in MM patients were estimated using Cox regression models in the univariate and multivariate analyses. Of the 623 patients recruited, 22 (3.5%) were diagnosed with proven or probable IFI. Light chain disease (adjusted hazard ratio [HR] 6.74, 95% confidence interval [CI] 2.10-21.66), hemoglobin less than 8 g/dl (adjusted HR 3.34, 95% CI 1.32-8.42), serum albumin < 3.5 g/dl (adjusted HR 3.24, 95% CI 1.09-9.68), and having received allogeneic stem cell transplantation (allo-SCT) (adjusted HR 5.98, 95% CI 1.62-22.03) were significantly associated with IFI in the multivariate analysis. Contracting IFI was in turn associated with early mortality (adjusted HR 11.60, 95% CI 1.26-106.74). Light chain disease, anemia, hypoalbuminemia, and receiving allo-SCT were independent predictors of IFI in MM patients. The early mortality risk is much higher in those encountering IFI. Physicians must be aware of the rare but potentially lethal infections.

Role of BMI and age in predicting pathologic vertebral fractures in newly diagnosed multiple myeloma patients: A retrospective cohort study.

Vertebral fractures affect approximately 30% of myeloma patients and lead to a poor impact on survival and life quality. In general, age and body mass index (BMI) are reported to have an important role in vertebral fractures. However, the triangle relationship among age, BMI, and vertebral fractures is still unclear in newly diagnosed multiple myeloma (NDMM) patients. This study recruited consecutive 394 patients with NDMM at Taipei Veterans General Hospital between January 1, 2005 and December 31, 2015. Risk factors for vertebral fractures in NDMM patients were collected and analyzed. The survival curves were demonstrated using Kaplan-Meier estimate. In total, 301 (76.4%) NDMM patients were enrolled in the cohort. In the median follow-up period of 18.0 months, the median survival duration in those with vertebral fractures ≥ 2 was shorter than those with vertebral fracture < 2 (59.3 vs 28.6 months; P = 0.017). In multivariate Poisson regression, BMI < 18.5 kg/m2 declared increased vertebral fractures compared with BMI ≥ 24.0 kg/m2 (adjusted RR, 2.79; 95% CI, 1.44-5.43). In multivariable logistic regression, BMI < 18.5 kg/m2 was an independent risk factor for vertebral fractures ≥ 2 compared with BMI ≥ 24.0 kg/m2 (adjusted OR, 6.05; 95% CI, 2.43-15.08). Among age stratifications, patients with both old age and low BMI were at a greater risk suffering from increased vertebral fractures, especially in patients > 75 years and BMI < 18.5 kg/m2 (adjusted RR, 12.22; 95% CI, 3.02-49.40). This is the first study that demonstrated that age had a significant impact on vertebral fractures in NDMM patients with low BMI. Elder patients with low BMI should consider to routinely receive spinal radiographic examinations and regular follow-up.

Risk of stroke in patients with newly diagnosed multiple myeloma: a retrospective cohort study.

Cerebrovascular events are a common complication among patients with cancer, increasing morbidity and mortality. However, the association between multiple myeloma and cerebrovascular events remains unclear. We therefore investigated multiple myeloma patients' risk factors for stroke to devise a better stroke-prevention strategy. This study includes consecutive patients 20 years and older who were newly diagnosed with symptomatic multiple myeloma at Taipei Veterans General Hospital, a tertiary medical center, between January 1, 2002 and December 31, 2014. The primary outcome was stroke development. Patients with head injuries, brain tumors, brain parenchymal invasions, or antecedent malignancies were excluded. Hazard ratios (HRs) of stroke risk factors for multiple myeloma patients were estimated by Cox proportional regression analysis. Overall, 395 patients with a median age of 70 years were investigated. In the median follow-up period of 18 months, cerebrovascular events occurred in 16 patients, including 10 ischemic strokes and 6 hemorrhagic strokes. The 5-year estimated cumulative incidence rate was 7.45%. In the multivariate analysis, the κ light chain isotype (adjusted HR, 8.37; 95% confidence interval [CI], 1.91-39.8), previous cerebrovascular accidents (adjusted HR, 5.16; 95% CI, 1.48-17.9), and serum creatinine > 2 mg/dL (adjusted HR, 4.21; 95% CI, 1.10-16.0) were identified as independent risk factors for stroke. Subgroup analysis showed that atrial fibrillation (adjusted HR, 8.07) and previous cerebrovascular accident (adjusted HR, 4.89) are significant risk factors for ischemic stroke. Serum creatinine > 2 mg/dL (adjusted HR, 30.6) and previous cerebrovascular accident (adjusted HR, 13.9) are significant for hemorrhagic stroke. Moreover, therapeutic strategies for multiple myeloma were not associated with stroke in our study. This study demonstrates that risk of stroke increases in myeloma patients with a κ light chain isotype, previous cerebrovascular events, and renal impairment. Further prospective clinical studies to clarify the relationship between multiple myeloma and stroke are warranted.

Clinical-associated characteristics and microbiological features of bloodstream nontyphoidal salmonella infection in adult patients receiving allogeneic hematopoietic stem cell transplantation.

Bloodstream nontyphoidal salmonella (NTS) infection is rare, but its associated characteristics and microbiological features in immunocompromised patients are worth paying attention to, particularly for those receiving allogeneic hematopoietic stem cell transplantation (SCT). No studies so far have analyzed post-transplant bloodstream NTS infection. Therefore, we reviewed 423 adult patients undergoing allogeneic hematopoietic SCT from 2003 to 2014. Nine out of four hundred twenty-three patients (2.13%) developed post-transplant bloodstream NTS infection, including two patients who had subsequent or combined metastatic infections. The median age at SCT was 35 years (interquartile range, 29-46) among the nine patients with bloodstream NTS infection. Male patients were predominant (78%). The median onset of bloodstream NTS infection was at 315 days after SCT (range, 207-629). Multivariate analysis revealed that extensive chronic graft-versus-host disease (GVHD) (OR 8.054, p = 0.003) and nonmyeloablative transplant conditioning (OR 4.604, p = 0.037) were significant associated characteristics for NTS infection. Currently, there are no published data analyzing and exploring post-transplant bloodstream NTS infections in adult allogeneic hematopoietic SCT. Our study determined the associated characteristics and microbiological features for this infection.