Background Targeting higher hemoglobin levels with erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk. Study ...Design Metaregression analysis examining the association of ESA dose with adverse outcomes independent of target or achieved hemoglobin level. Setting & Population Patients with anemia of CKD irrespective of dialysis status. Selection Criteria for Studies We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for the treatment of anemia in adults with CKD, with a minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis. Predictors ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels. Outcomes All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression, or transfusion requirement. Results 31 trials (12,956 patients) met the criteria. All-cause mortality was associated with higher (per epoetin alfa–equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio IRR, 1.42; 95% CI, 1.10-1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02-1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin level (IRR, 1.48; 95% CI, 1.02-2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin level (IRR, 1.41; 95% CI, 1.08-1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction, but not statistically significant. Higher total-study-period mean ESA dose also was associated with increased rate of hypertension, stroke, and thrombotic events, including dialysis vascular access–related thrombotic events. Limitations Use of study-level aggregated data; use of epoetin alfa–equivalent doses; lack of adjustment for confounders. Conclusions In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin level.
While germline and somatic mutations in the gene PTPN11, encoding a phosphatase which regulates the RAS signaling pathway, are well characterized in children with Noonan syndrome and juvenile ...myelomonocytic leukemia, less is known about their clinical impact in adults with acute myeloid leukemia (AML). To elucidate the effect of PTPN11 mutations (PTPN11
) on clinical outcomes, we screened adult patients with AML treated at our institution using targeted next-generation sequencing. Among 1406 consecutive patients, 112 (8%) had PTPN11
. These mutations were more commonly associated with the acute myelomonocytic/monocytic leukemia subtype than was wild-type PTPN11, while none were detected in patients with core-binding factor AML. They co-occurred more commonly with NPM1 mutations and FLT3 internal tandem duplications and less commonly with mutations in IDH2 and a complex karyotype. Compared with the wild-type allele, PTPN11
was associated with lower complete response rates (54% vs 40%; P = 0.04), and shorter overall survival (median 13.6 vs 8.4 months; P = 0.008). In a multivariate analysis, PTPN11
independently increased the risk of death, with a hazard ratio of 1.69 (95% CI, 1.25-2.29; P = 0.0007). In summary, mutations in PTPN11 have a characteristic phenotype in adults with AML and are associated with an adverse prognosis.
Azacitidine, a hypomethylating agent, has caused a paradigm shift in the outcomes of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who are not eligible for stem cell ...transplantation, particularly in combination with BCL2 and IDH inhibitors. Azacitidine and Azacitidine-based combinations have been widely considered a safe low-intensity therapy when compared to traditional conventional treatments. The development of lung toxicity from azacitidine is not a well-characterized adverse event. However, if it happens, it can be fatal, especially if not recognized and treated promptly. In this review, we aim to familiarize the reader with the presentation of azacitidine-induced lung injury, provide our suggested approach to management based on our experience and the current understanding of its mechanism, and review the literature of 20 case reports available on this topic.
Abstract
Background
The majority of studies that provide insights into the influence of the microbiome on the health of hematologic malignancy patients have concentrated on the transplant setting. ...Here, we sought to assess the predictive capacity of the gastrointestinal microbiome and its relationship to infectious outcomes in patients with acute myeloid leukemia (AML).
Methods
16s rRNA-based analysis was performed on oral swabs and stool samples obtained biweekly from baseline until neutrophil recovery following induction chemotherapy (IC) in 97 AML patients. Microbiome characteristics were correlated with clinical outcomes both during and after IC completion.
Results
At the start of IC, higher stool Shannon diversity (hazard ratio HR, 0.36; 95% confidence interval CI, .18–.74) and higher relative abundance of Porphyromonadaceae (HR, 0.36; 95% CI, .18–.73) were associated with increased probability of remaining infection-free during neutropenia. A baseline stool Shannon diversity cutoff of <2 had optimal operating characteristics for predicting infectious complications during neutropenia. Although 56 patients received therapy >72 hours with a carbapenem, none of the patients had an infection with an extended spectrum β-lactamase–producing organism. Patients who received carbapenems for >72 hours had significantly lower α-diversity at neutrophil recovery (P = .001) and were approximately 4 times more likely to have infection in the 90 days following neutrophil recovery (HR, 4.55; 95% CI, 1.73–11.93).
Conclusions
Our results suggest that gut microbiome evaluation could assist with infectious risk stratification and that improved targeting of antibiotic administration during IC could decrease subsequent infectious complications in AML patients.
Baseline microbiome diversity is a strong independent predictor of infection during acute myeloid leukemia induction chemotherapy (IC) among clinical and microbiome covariates. Higher baseline levels of Porphyromonadaceae appear protective against infection, while carbapenem use is associated with consequences to the microbiome and infection susceptibility post-IC.
Background Case series suggest that long-term use of proton pump inhibitors (PPIs) is associated with hypomagnesemia, but the current literature lacks systematically collected data. Our aim was to ...examine whether hypomagnesemia at the time of hospital admission is associated with out-of-hospital use of PPIs. Study Design Nested case-control study matched for age and sex. Setting & Participants Data were collected retrospectively from a tertiary acute-care facility. Eligible cases consisted of 402 adults with hypomagnesemia (serum magnesium <1.4 mEq/L) at the time of hospital admission to medical services, age- and sex-matched with 402 control individuals with normal serum magnesium levels (1.4-2.0 mEq/L). Predictor Out-of-hospital PPI use was identified in the hospital record. An omeprazole equivalent dose was calculated when possible. Covariates included the Charlson-Deyo comorbidity index, diabetes, diuretic use, estimated glomerular filtration rate, and gastroesophageal reflux. Outcome Multivariable conditional logistic regression analyses were used to examine the association of PPI use with hypomagnesemia at the time of hospital admission. Results PPI use was not associated with hypomagnesemia (adjusted OR, 0.82; 95% CI, 0.61-1.11). Neither PPI type nor omeprazole equivalent daily dose was associated with hypomagnesemia. Sensitivity analyses of PPI use restricted to patients with esophageal disorders (adjusted OR, 1.00; 95% CI, 0.69-1.45), severe hypomagnesemia (magnesium, ≤1.0 mEq/L; adjusted OR, 0.78; 95% CI, 0.13-4.61), or estimated glomerular filtration rate ≥60 mL/min/1.73 m2 (adjusted OR, 0.84; 95% CI, 0.53-1.34) were unrevealing. Limitations Exposure misclassification; hospitalized patients on medical services may not be representative of a broader ambulatory-based population. Conclusions In a hospital-based adult population, out-of-hospital PPI use is not associated with hypomagnesemia at the time of hospital admission to medical services. In light of these inconclusive results, prospective cohort studies are needed to address this rare potential medication-related adverse effect.
OBJECTIVEWe herein describe two cases of de novo lymphoid blastic transformation in patients with no history of chronic-phase chronic myeloid leukemia (CP-CML), both of whom were labeled initially as ...Philadelphia positive B-Acute Lymphoblastic Leukemia (B-ALL). METHODSThe first patient was an 18-year-old male who presented with subjective fever, intentional weight loss, generalized fatigue, and headache. Investigations showed leukocytosis (312 × 10^3/ul), thrombocytopenia and anemia. Flowcytometry was consistent with B-ALL, with aberrant expression of CD13 and CD33. He was found to be positive for BCR::ABL by FISH, and karyotype confirmed the presence of the Philadelphia chromosome. He received a pediatric-inspired regimen and achieved remission with negative measurable residual disease (MRD) by flowcytometry, however with persistent cytogenetic abnormality using FISH for BCR::ABL. FISH abnormality was confirmed to be in the myeloid compartment using myeloid segregated FISH, reclassifying the disease to de novo lymphoid blastic phase CML. The second patient was a 52-year-old male who presented with fever and shortness of breath. Bilateral cervical lymphadenopathy and hepatosplenomegaly were identified on examination, and investigations showed leukocytosis (371 × 10^3/ul), anemia, and thrombocytopenia. BCR::ABL rearrangement was identified by FISH, molecular testing, and confirmed with karyotype. He was treated with Mini-CVD and Ponatinib, achieved complete remission with negative MRD by flow cytometry, however molecular studies showed BCR-ABL1 level at 58% IS indicating a persistent cytogenetic abnormality. RESULTSDe novo lymphoid blastic-phase CML can therefore be difficult to differentiate from Philadelphia positive B-ALL due to their overlapping clinical and laboratory picture, implying the need to do myeloid compartment evaluation at the time of diagnosis. CONCLUSIONWith recent progress in the treatment of Philadelphia positive B-ALL, including the role of transplant with the use of novel agents, a better characterization of this disease entity in retrospective and prospective trials is warranted.
Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45-55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > ...85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined.
We retrospectively reviewed patients with FLT3-mutated AML between November 2006 and December 2019.
In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first (n = 56), second (n = 32), and third FLT3i-based (n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n = 183), second (n = 89), and third/fourth (n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i (n = 21) versus FLT3i-based combinations (n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i (n = 82) versus FLT3i-based combinations (n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i (n = 63) versus FLT3i-based combinations (n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively.
CRc rates drop progressively with sequential exposure to FLT3i's in FLT3-mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.
Abstract Background Therapeutic hypothermia has been shown to reduce neurological morbidity and mortality in the setting of out-of-hospital cardiac arrest and may be beneficial following brain injury ...and cardiopulmonary bypass. We conducted a systematic review to ascertain the effect of therapeutic hypothermia on development of acute kidney injury (AKI) and mortality. Methods We searched for randomized controlled trials in MEDLINE through February 2011. We included trials comparing hypothermia to normothermia that reported kidney-related outcomes including, development of AKI, dialysis requirement, changes in serum creatinine, and mortality. We performed Peto fixed-effect and random-effects model meta-analyses, and meta-regressions. Results Nineteen trials reporting on 2218 patients were included; in the normothermia group, the weighted rate of AKI was 4.2%, dialysis requirement 3.7%, and mortality 10.8%. By meta-analysis, hypothermia was not associated with a lower odds of AKI (odds ratio OR 1.01, 95% confidence interval CI 0.68, 1.51; P = 0.95) or dialysis requirement (OR 0.81; 95% CI 0.30, 2.19; P = 0.68); however, by meta-regression, a lower target cooling temperature was associated with a lower odds of AKI ( P = 0.01). Hypothermia was associated with lower mortality (OR 0.69; 95% CI 0.51, 0.92; P = 0.01). Conclusions In trials that ascertained kidney endpoints, therapeutic hypothermia prevented neither the development of AKI nor dialysis requirement, but was associated with lower mortality. Different definitions and rates of AKI, differences in mortality rates, and concerns about the optimal target cooling temperature preclude definitive conclusions.
PDF
