Gabriela Hobbs

Sequence-Based Discovery of Bradyrhizobium enterica in Cord Colitis Syndrome

BACKGROUND Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin. METHODS We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls. RESULTS DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease. CONCLUSIONS We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen. (Funded by the National Cancer Institute and others.)

Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that is associated with a substantial symptom burden, thrombohemorrhagic complications, and impaired survival. A decade after the seminal discovery of an activating mutation in the tyrosine kinase JAK2 in nearly all patients with PV, new treatment options are finally beginning to emerge, necessitating a critical reappraisal of the underlying pathogenesis and therapeutic modalities available for PV. Herein, we comprehensively review clinical aspects of PV including diagnostic considerations, natural history, and risk factors for thrombosis. We summarize recent studies delineating the genetic basis of PV, including their implications for evolution to myelofibrosis and secondary acute myeloid leukemia. We assess the quality of evidence to support the use of currently available therapies, including aspirin, phlebotomy, hydroxyurea, and interferon. We analyze recent studies evaluating the safety and efficacy of JAK inhibitors, such as ruxolitinib, and evaluate their role in the context of other available therapies for PV. This review provides a framework for practicing hematologists and oncologists to make rational treatment decisions for patients with PV.

Effects of T-Cell Depletion on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in AML Patients

Graft versus host disease (GVHD) remains one of the leading causes of morbidity and mortality associated with conventional allogeneic hematopoietic stem cell transplantation (HCT). The use of T-cell depletion significantly reduces this complication. Recent prospective and retrospective data suggest that, in patients with AML in first complete remission, CD34+ selected grafts afford overall and relapse-free survival comparable to those observed in recipients of conventional grafts, while significantly decreasing GVHD. In addition, CD34+ selected grafts allow older patients, and those with medical comorbidities or with only HLA-mismatched donors to successfully undergo transplantation. Prospective data are needed to further define which groups of patients with AML are most likely to benefit from CD34+ selected grafts. Here we review the history of T-cell depletion in AML, and techniques used. We then summarize the contemporary literature using CD34+ selection in recipients of matched or partially mismatched donors (7/8 or 8/8 HLA-matched), and provide a summary of the risks and benefits of using T-cell depletion.

Myeloproliferative neoplasms, version 2.2018 featured Updates to the NCCN guidelines

Myeloproliferative neoplasms (MPNs) are a group of heterogeneous disorders of the hematopoietic system that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). PV and ET are characterized by significant thrombohemorrhagic complications and a high risk of transformation to MF and acute myeloid leukemia. The diagnosis and management of PV and ET has evolved since the identification of mutations implicated in their pathogenesis. These NCCN Guideline Insights discuss the recommendations outlined in the NCCN Guidelines for the risk stratification, treatment, and special considerations for the management of PV and ET.

The Development and Use of Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

Following the discovery of the JAK2V617F mutation, Janus kinase (JAK) 2 inhibitors were developed as rationally designed therapy in myeloproliferative neoplasms (MPNs). Although JAK2 inhibitors have clinical efficacy in MPN, they are not clonally selective for the JAK2V617F-mutant cells. Because activated JAK-signal transducer and activator of transcription (STAT) signaling is a common feature of MPN, JAK2 inhibitors are efficacious regardless of the specific MPN phenotypic driver mutation. The Food and Drug Administration approved the JAK1/JAK2 inhibitor, ruxolitinib, for the treatment of myelofibrosis and polycythemia vera. Additional JAK2 inhibitors are currently in advanced phased clinical trials.

Clinical and molecular genetic characterization of myelofibrosis.

Purpose of reviewThe myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. Of these, myelofibrosis often has the most aggressive course. There is, however, often significant clinical heterogeneity among patients with myelofibrosis. We seek to summarize recent clinical and biological findings in myelofibrosis as well as review the spectrum of clinically relevant mutation in myelofibrosis and their implications. Recent findingsThe mutational spectrum in myelofibrosis includes driver mutations in genes such as JAK2, calreticulin, and myeloproliferative leukemia virus oncogene. In addition, recurrent mutations in epigenetic modifiers such as ASXL1 and TET2 have also been described. Importantly, several studies have indicated that specific mutations, as well as the number of mutations, that a patient bears may have important clinical consequences. The presence or absence of certain mutations may help to determine a patients risk for thrombosis, leukemic transformation, and survival. SummaryMyelofibrosis often has variable outcomes among patients. Prognostic systems based on clinical observations have been developed in an attempt to predict risks of disease progression and transformation. The discovery of recurrent genomic alterations in myelofibrosis, and the observation that many of these alterations may help predict clinical outcomes, has heralded a new era in the biologic understanding and clinical approach to myelofibrosis.

Association between insurance status at diagnosis and overall survival in chronic myeloid leukemia: A population-based study

Chronic myeloid leukemia (CML) can be treated effectively with tyrosine kinase inhibitor therapy directed at BCR‐ABL, but access to care, medication cost, and adherence may be barriers to treatment. This study was designed to determine whether the insurance status at diagnosis influences CML patient outcomes.

Risk and timing of cardiovascular death among patients with myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders associated with progression to leukemia and poor survival. Clonal hematopoiesis in people without an MDS diagnosis carries an increased risk of cardiovascular death. Many clonally restricted mutations are shared between patients with MDS and those with non-MDS clonal hematopoiesis; therefore, we evaluated the risk of cardiovascular death among patients with MDS. We evaluated adults with MDS in the Surveillance, Epidemiology, and End Results database of the National Cancer Institute and compared them with the general population living in the same states. We grouped histological subtypes of MDS into lower-, intermediate-, and higher-risk disease. The primary outcomes were overall survival and primary cause of death (COD) as reported to state registries. A total of 21 372 patients with MDS between 2001 and 2011 died during follow-up with a known COD. The rate of death due to cardiovascular disease (CVD) was 4613 per 100 000 person-years, compared with 2091 in the age- and-sex-adjusted US population (standardized mortality ratio, 2.21). At 24 months, the cumulative incidence of death attributed to MDS or leukemia was 23% vs 8% for CVD. Among those alive at 60 months, 27% eventually died of CVD compared with 29% from MDS or leukemia; those with lower-risk disease who survived >60 months had more deaths attributed to cardiovascular causes (30%; 95% confidence interval [CI], 26.7-33.2%) than MDS itself (24%; 95% CI, 21.4-27.5%). Patients with MDS are more likely to die of cardiovascular causes than the general population. Modifying cardiovascular risk factors, especially among those with lower-risk disease, may be warranted for MDS-related clinical care.

Potentially avoidable hospital admissions in older patients with acute myeloid leukaemia in the USA: a retrospective analysis

BACKGROUND Older adults (≥60 years of age) with acute myeloid leukaemia spend a substantial proportion of their life in hospital after diagnosis. We examined reasons for their hospital admissions and identified potentially avoidable hospital admissions (PAH) in this age group in the USA. METHODS In this retrospective analysis, we examined the reasons for hospital admissions in older patients diagnosed with and treated for acute myeloid leukaemia at two tertiary care hospitals in the USA. We included patients receiving intensive induction chemotherapy or non-intensive treatment. We excluded those with acute promyelocytic leukaemia, those seen only for a one-time consultation who received primary treatment elsewhere, and those who received supportive care alone. We identified the eligible cohort using the Dana-Farber Cancer Institute and Massachusetts General Hospital Leukemia Clinical Research Information Systems database. Practising oncologists used a consensus-driven medical record review process to identify the primary reason for each hospital admission and categorise it as potentially avoidable or not avoidable on the basis of an adaptation of Grahams criteria for PAH. We used multivariable logistic regression analyses to identify predictors of PAH. FINDINGS Between May 1, 2005, and Dec 23, 2011, we assessed 1040 hospital admissions (excluding initial admission for diagnosis) in 329 consecutively admitted patients. The most common primary reasons for hospital admissions were: fever or infection (396 [38%]), planned admission for chemotherapy or transplantation (391 [38%]), and uncontrolled symptoms (102 [10%]). We identified 172 (27%) of 649 unplanned hospital admissions as potentially avoidable; among these admissions, 82 (48%) were readmissions because of previous premature hospital discharge, 32 (19%) because of problems that could have been managed in the outpatient setting, and 26 (15%) because of failure of timely outpatient follow-up. In a mixed logistic regression model, higher education (odds ratio 1·43 [95% CI 1·01-2·00]; p=0·04) and receipt of non-intensive induction chemotherapy (1·97 [1·25-3·10]; p=0·003) were predictors of PAH. INTERPRETATION Although many hospital admissions in older patients with acute myeloid leukaemia are unavoidable and driven by the illness course and its treatment, a substantial proportion are potentially avoidable. Future interventions to reduce PAH in this population are clearly warranted. FUNDING National Cancer Institute, National Palliative Care Research Center, and Cambia Health Foundation.

A population-based analysis of second malignancies among patients with myeloproliferative neoplasms in the SEER database

Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) including myelofi brosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), can transform into acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) [1,2], and have been associated with a greater incidence of lymphoid neoplasms [3]. Epidemiologic data suggests increased incident non-hematologic malignancies among MPN patients [4 – 8], although the magnitude of risk is debated [5]. One study of 7229 patients with ET, PV, or chronic myeloid leukemia (CML), with median follow-up of 4 – 5 years, found a modestly increased risk of developing a second non-hematologic malignancy (standardized incidence ratio 1.2 – 1.4) compared to the age-adjusted general population [6]. Another study of 733 patients, with median follow-up of 6.45 years, found no increase in second non-hematologic malignancies, aside from melanoma [5]. Th erefore, the true second malignancy rate in this population remains unclear, which can impact optimal counseling to these patients. Th e Surveillance, Epidemiology, and End Results Program (SEER) Registry of the National Cancer Institute is a recognized standard for population-based cancer epidemiology in the United States, capturing approximately 28% of the population. Our objective was to determine the cumulative incidence of second malignancies among patients in the SEER database whose fi rst malignancy is an MPN, and compare this rate to the age-adjusted US population cancer rate. We used the SEER 18 registries database released in April 2014 (1973 – 2011; November 2013 submission). SEER included MPNs starting in 2001; we included patients diagnosed with an MPN as their fi rst cancer, between 2001 and 2011, according to ICD-O-3 codes: PV (code 9950), chronic myeloproliferative disease, NOS (9960), MF (9961), and ET (9962). Diagnoses are confi rmed pathologically according to WHO 2008 criteria and the International Classifi cations of Diseases for Oncology, Version 3 [1,9]. CML patients were excluded. Time to second malignancy was calculated by subtracting second malignancy survival/follow-up time from MPN survival/follow-up time. We classifi ed second malignancy according to SEER site-specifi c categories. Th e second malignancy incidence rate was the number of second cancers per person-years of follow-up. Site-specifi c malignancies could occur at any point in follow-up; these, therefore, may not be the immediate subsequent malignancy for a patient. Death was a competing risk. Age-adjusted malignancy incidence rates for the general population were calculated by weighting cancer incidence rates provided by the National Cancer Institute, SEER Cancer Statistic Review 2007 – 2011, according to the age distribution of the SEER MPN population. Incident leukemia cases included AML, biphenotypic and undiff erentiated acute leukemia, and MDS. Non-leukemic second malignancy rates were calculated by subtracting these cases, as well as cases of progression to another MPN. SEER documents radiation therapy but does not report chemotherapy data. Radiation given concurrently or following the original MPN diagnosis, and prior to AML/MDS diagnosis, was a variable in subgroup analysis. Demographic characteristics were compared using Chisquare and Fisher ’ s exact test. Cumulative incidences of second malignancies were calculated at 60 and 120 months using the %CIF macro package in SAS 9.4 (Cary, NC, USA), using the method of Fine and Gray. Age-adjusted cancer incident rate ratios for MPN patients compared to the 2007 – 2011 population were calculated using STATA version 9.1 (College Station, TX, USA). Overall survival (OS) was defi ned as time from MPN diagnosis to death, censored at last known alive, and estimated using the method of Kaplan and Meier. Cox regression was performed to calculate predictors of overall survival. Cumulative incidence of second malignancies was modeled using the subdistribution hazard, with death as a competing risk, by the %PSHREG macro package in SAS 9.4. All p -values are considered signifi cant at the two-sided 0.05 level. We identifi ed 20,250 MPN patients diagnosed between January 2001 and December 2011, with 81,995.5 person-years follow-up; median follow-up was 42 months. Median age of diagnosis was 63 for PV, 66 for ET, 69 for MF, and 71 for MPN Leukemia & Lymphoma, 2016; 57(5): 1197–1200 May