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1.  Females with FVIII and FIX deficiency have reduced joint range of motion 
American journal of hematology  2014;89(8):831-836.
Little is known about rates of joint bleeding among females with FVIII/FIX deficiency or hemophilia carriers. In a cross-sectional study, we tested the hypothesis that females with FVIII or FIX deficiency enrolled in the Universal Data Collection (UDC) project had a reduced mean overall joint range of motion (ROM) compared with historic controls from the Normal Joint Study. Demographics, clinical characteristics, and joint ROM measurements on 303 females without a bleeding disorder and 148 females with FVIII and FIX deficiency, respectively, between the ages of 2–69 years and a body mass index (BMI) ≤35 were compared. Multivariate linear regression was performed with the overall joint ROM (sum of the right and left ROM measurements of five joints) as the dependent variable and FVIII or FIX activity as the independent variable adjusting for age, race, BMI, and number of joint bleeds reported over the last 6 months. As FVIII and FIX activity decreased, the mean overall joint ROM became reduced and in most cases was significantly lower than that of the controls regardless of age and clinical hemophilia severity. Further investigation of reduced joint ROM as evidence of subclinical joint bleeding in females with FVIII and FIX deficiency is warranted.
PMCID: PMC4477796  PMID: 24838518
2.  Cytogenetic Risk Stratification of 417 Patients with Chronic Myelomonocytic Leukemia from a Single Institution 
American journal of hematology  2014;89(8):813-818.
Approximately 30% of patients with chronic myelomonocytic leukemia (CMML) have karyotypic abnormalities and this low frequency has made using cytogenetic data for the prognostication of CMML patients challenging. Recently, a three-tiered cytogenetic risk stratification system for CMML patients has been proposed by the Spanish study group. Here we assessed the prognostic impact of cytogenetic abnormalities on overall survival (OS) and leukemia-free survival (LFS) in 417 CMML patients from our institution. Overall, the Spanish cytogenetic risk effectively stratified patients into different risk groups, with a median OS of 33 months in the low-, 24 months in intermediate- and 14 months in the high-risk groups. Within the proposed high risk group; however, marked differences in OS were observed. Patients with isolated trisomy 8 showed a median OS of 22 months, similar to the intermediate-risk group (p=0.132), but significantly better than other patients in the high-risk group (p=0.018). Furthermore, patients with more than 3 chromosomal abnormalities showed a significantly shorter OS compared with patients with 3 abnormalities (8 vs. 15 months, p=0.004), suggesting possible a separate risk category. If we simply moved trisomy 8 to the intermediate risk category, the modified cytogenetic grouping would provide a better separation of OS and LFS; and its prognostic impact was independent of other risk parameters. Our study results strongly advocate for the incorporation of cytogenetic information in the risk model for CMML.
PMCID: PMC4354712  PMID: 24782398
Chronic myelomonocytic leukemia (CMML); Cytogenetics risk classification; Overall survival; trisomy 8; complex karyotype
3.  A phase I dose escalation study of oral bexarotene in combination with intravenous decitabine in patients with AML 
American journal of hematology  2014;89(8):E103-E108.
The response rate of non-M3 AML to all trans retinoic acid (ATRA) has been limited. Using Affymetrix expression arrays, we found that in diverse AML blasts RXRA was expressed at higher levels than RARA and that mouse Ctsg-PML-RARA leukemia responded to bexarotene, a ligand for RXRA. We therefore performed a phase I study of combination bexarotene and decitabine in elderly and relapsed AML patients. We found that this combination was well tolerated, although outcomes were modest (1 CRi, and 3 PR among 19 patients). Correlative studies found that patients with clinical response had increased differentiation to bexarotene both in vivo and ex vivo, suggesting that pre-treatment analysis might identify a more susceptible subgroup of patients.
PMCID: PMC4108244  PMID: 24723466
4.  Mutation analysis of a cohort of US patients with hemophilia B 
American journal of hematology  2014;89(4):375-379.
Hemophilia B (HB) is a disorder resulting from genetic mutations in the Factor 9 gene (F9). Genotyping of HB patients is important for genetic counseling and patient management. Here we report a study of mutations identified in a large sample of HB patients in the US. Patients were enrolled through an inhibitor surveillance study at 17 hemophilia treatment centers. A total of 87 unique mutations were identified from 225 of the 226 patients, including deletions, insertions, and point mutations. Point mutations were distributed throughout the F9 gene and were found in 86% of the patients. Of these mutations, 24 were recurrent in the population, and 3 of them (c.316G>A, c.1025C>T, and c.1328T>A) accounted for 84 patients (37.1%). Haplotype analysis revealed that the high recurrence arose from a founder effect. The severity of HB was found to correlate with the type of mutation. Inhibitors developed only in severe cases with large deletions and nonsense mutations. None of the mild or moderate patients developed inhibitors. Our results provide a resource describing F9 mutations in US HB patients and confirm previous findings that patients bearing large deletions and nonsense mutations are at high risk of developing inhibitors.
PMCID: PMC4504203  PMID: 24375831
5.  Risk of diffuse large B-cell lymphoma after solid organ transplantation in the United States 
American journal of hematology  2014;89(7):714-720.
Non-Hodgkin lymphoma (NHL) arising in the context of immunosuppression is an important adverse outcome following solid organ transplantation. Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed subtype of post-transplant NHL, but few studies of transplant recipients have examined subtype-specific risks. Therefore, we examined DLBCL risk in the Transplant Cancer Match Study, including registry-based cancer ascertainment among 96,615 solid organ transplants performed from 2000–2008. We determined standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) comparing DLBCL risk in transplant recipients to that in the general population, and used multivariable Poisson regression models to assess the impact of potential risk factors. We identified 321 incident cases of DLBCL, over 12 times more than expected based on general population rates (SIR=12.6, 95% CI=11.2–14.0). SIRs were highest in young recipients and those receiving a lung or pancreas/kidney-pancreas transplant, and were greatly elevated for extranodal DLBCLs at the site of the transplant compared to other sites. DLBCL risk was highest in the first year following transplant, and SIRs for early-onset DLBCL risk were elevated in association with EBV negative serostatus and use of polyclonal antibody induction therapy. In conclusion, associations between recipient and transplant factors and post-transplant DLBCL risk suggest a complicated interrelationship among multiple risk factors and timing of disease.
PMCID: PMC4069221  PMID: 24753070
organ transplant; non-Hodgkin lymphoma; diffuse large B-cell lymphoma; immunosuppression; Epstein-Barr virus
6.  Genomic ancestry and somatic alterations correlate with age at diagnosis in Hispanic children with B-cell ALL 
American journal of hematology  2014;89(7):721-725.
Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) than non-Hispanic whites, but tend to be diagnosed at older ages. In genome-wide association studies, Native American ancestry and polymorphisms in six genes have been associated with ALL risk.
In multivariable regression models, we investigated whether genomic ancestry, inherited risk SNPs, or acquired somatic alterations were associated with differences in age at diagnosis in Hispanic children with B-cell ALL. Genome-wide array data were used to estimate each participant's percent membership in the three Hispanic ancestral populations: Native American, African, and European.
Each 20% increase in European ancestry was associated with a six month younger age at diagnosis (95% CI=0.36-11.6 months, P=0.037). Correspondingly, each 20% increase in Native American ancestry was associated with a six month older age at diagnosis (P=0.037). Both the TEL-AML1 translocation and high-hyperdiploidy were associated with younger age at diagnosis (24.4 months, P=2.0×10−4 and 12.4 months, P=0.011, respectively), while CDKN2A and IKZF1 deletions were associated with older age at diagnosis (19.7 months, P=7.0×10−4 and 18.1 months, P=0.012, respectively). No associations with age at diagnosis were observed for RAS mutation, PAX5 deletion or for known heritable risk alleles in IKZF1, CDKN2A, PIP4K2A, GATA3, ARID5B or CEBPE.
Because younger age at diagnosis is associated with improved treatment outcomes for children with ALL, the effect of European ancestry on ALL survival may be mediated by its effect on age at diagnosis, or by proxy, its association with more treatable molecular subtypes of ALL.
PMCID: PMC4069235  PMID: 24753091
Childhood acute lymphoblastic leukemia; Hispanics; ancestry; genetic association; admixture
7.  National surveillance for hemophilia inhibitors in the United States: Summary report of an expert meeting 
American journal of hematology  2014;89(6):621-625.
On March 12, 2012, the Centers for Disease Control and Prevention (CDC) held a meeting of its partners in hemophilia treatment, community-based organizations, industry, and government to review data and discuss implementation issues relevant to planned United States (U.S.) national inhibitor surveillance. Issues discussed included the current status of inhibitor surveillance in the United Kingdom (UK) and the US, the results of a US inhibitor surveillance feasibility study, proposed national surveillance schemes, laboratory testing and reporting issues and potential opportunities for future inhibitor-related research. It was concluded that implementation of a national program of inhibitor surveillance using standardized testing through an established public health registry along with patient and care provider education and targeted research provide the best opportunity to inform efforts to develop and evaluate effective prevention strategies.
PMCID: PMC4472332  PMID: 24616187
8.  Phase II Study of Bryostatin 1 and Vincristine for Aggressive Non-Hodgkin Lymphoma Relapsing after an Autologous Stem Cell Transplant 
American journal of hematology  2009;84(8):484-487.
Bryostatin 1, isolated from a marine bryozoan, enhances the efficacy of cytotoxic agents through modulation of the protein kinase C pathway and is active in combination with vincristine for diffuse large B-cell lymphoma. Further, the apoptotic frequency of peripheral blood T lymphocytes as determined by flow cytometry may predict which patients will respond to this combination. We tested the efficacy and safety of bryostatin 1 50μg/m2 given over 24 hours and vincristine 1.4 mg/m2 on days 1 and 15 every 28 days in aggressive B-cell non-Hodgkin lymphoma relapsing after autologous stem cell transplantation. End points included tumor response, toxicity and survival. Responses were correlated with an increase in apoptotic frequency of CD5+ cells by flow cytometry using annexin V staining. Fourteen patients were enrolled with 13 being evaluable for a response. The overall response rate was 31% with 2 patients achieving a complete response. The most common toxicities were grade 3 lymphopenia (7 patients), grade 3 to 4 neutropenia (2 patients), and grade 3 hypophosphatemia (2 patients). Median progression-free and overall survivals for all patients were 5.7 and 21.4 months respectively. One patient demonstrated an increase in T-cell apoptotic frequency, also achieving a complete response. Bryostatin 1 and vincristine has efficacy in select patients with aggressive non-Hodgkin lymphoma. Future investigations of agents targeting the protein kinase C pathway may benefit from early response assessment using flow cytometry to evaluate T-cell apoptosis.
PMCID: PMC4465083  PMID: 19536846
bryostatin 1; vincristine; protein kinase C; non-Hodgkin lymphoma
9.  White Blood Cell Recovery After Allogeneic Hematopoietic Cell Transplantation Predicts Clinical Outcome 
American journal of hematology  2014;89(6):591-597.
To determine whether outcome after allogeneic hematopoietic cell transplantation (HCT) could be estimated by using peripheral white blood cell count (WBC) as a metric that integrates several aspects of HCT recovery, we conducted a retrospective study of 1109 adult patients who underwent first allogeneic HCT from 2003 through 2009. WBC at 1, 2, and 3 months after HCT was categorized as low (<2), normal (2-10), and high (>10×109 cells/L). Overall survival (OS) and progression-free survival (PFS) were lower for patients with low or high WBC at 1, 2, or 3 months after HCT (p<0.0001). We developed a predictive 3-group risk model based on the pattern of WBC recovery early after HCT. Five-year OS was 47%, 30%, and 15% (p<0.0001) and 5-year PFS was 39%, 22%, and 14% for patients in the 3 different risk groups (p<0.0001). The pattern of WBC recovery early after HCT provides prognostic information for relapse, non-relapse mortality, progression-free survival, and overall survival. A scoring system based on the trajectory of the WBC in the first 3 months after HCT can effectively stratify patients into 3 groups with different PFS and OS. If validated, this system could be useful in the clinical management of patients after HCT, and to stratify patients enrolled on HCT clinical trials.
PMCID: PMC4031274  PMID: 24549932
White blood cell count; Allogeneic transplantation; Prognostic risk group
10.  Prolonged Cyclosporine Administration After Antithymocyte Globulin Delays But Does Not Prevent Relapse in Severe Aplastic Anemia 
American journal of hematology  2014;89(6):571-574.
In severe aplastic anemia, approximately one-third of responders to standard horse antithymocyte globulin (h-ATG) plus cyclosporine (CsA) will relapse. Anecdotal experience has suggested that a gradual CsA taper might avoid relapse, but this practice has not been rigorously assessed prospectively. In 2003, we adopted a strategy to taper CsA beyond 6 months, with the intention to reduce hematologic relapse compared to our extensive historical experience. In total, 102 patients received h-ATG/CsA for 6 months in two sequential clinical protocols: 67 patients (66%) responded and all had the CsA dose tapered per protocol over the subsequent 18 months (total of 2 years). The rate of relapse at 5 years was 33% (95% CI 27%-44%), which did not differ from our large historical relapse experience (patients treated before 2003) of 30-40%, in protocols in which CsA was simply discontinued at 6 months. However, time to relapse was prolonged by about 1 year with the longer CsA course. The rates of clonal evolution and overall survival did not differ between the two cohorts. We infer from this large prospective study that CsA taper as implemented delayed but did not prevent relapse. The kinetics of relapse with long course CsA does suggest that a lower long-term dose might be adequate to maintain patients in remission.
PMCID: PMC4074770  PMID: 24971433
11.  Genetic polymorphisms in oxidative stress related genes are associated with outcomes following treatment for aggressive B-cell non-Hodgkin lymphoma 
American journal of hematology  2014;89(6):639-645.
Variable survival outcomes are seen following treatment for aggressive non-Hodgkin lymphoma (NHL). This study examined whether outcomes for aggressive B-cell NHL are associated with single nucleotide polymorphisms (SNPs) in oxidative stress-related genes, which can alter drug metabolism and immune responses. Genotypes for 53 SNPs in 29 genes were determined for 337 patients given anthracycline-based therapies. Their associations with progression-free survival (PFS) and overall survival (OS) were estimated by Cox proportional hazard regression; associations with hematologic toxicity were estimated by logistic regression. To validate the findings, the top 3 SNPs were tested in an independent cohort of 572 DLBCL patients. The top SNPs associated with PFS in the discovery cohort were the rare homozygotes for MPO rs2243828 (hazard ratio [HR]=1.87, 95% confidence interval [CI]=1.14–3.06, P = 0.013), AKR1C3 rs10508293 (HR=2.09, 95% CI=1.28–3.41, P=0.0032) and NCF4 rs1883112 (HR=0.66, 95% CI=0.43–1.02, P=0.06). The association of the NCF4 SNP with PFS was replicated in the validation dataset (HR=0.66, 95% CI=0.44–1.01, P=0.05) and the meta-analysis was significant (HR=0.66, 95% CI=0.49–0.89, P<0.01). The association of the MPO SNP was attenuated in the validation dataset, while the meta-analysis remained significant (HR=1.64, 95% CI=1.12–2.41). These two SNPs showed similar trends with OS in the meta-analysis (for NCF4, HR=0.72, 95% CI 0.51–1.02, P=0.07 and for MPO, HR=2.06, 95% CI 1.36–3.12, P<0.01). In addition, patients with the rare homozygote of the NCF4 SNP had an increased risk of hematologic toxicity. We concluded that genetic variations in NCF4 may contribute to treatment outcomes for patients with aggressive NHL.
PMCID: PMC4137041  PMID: 24633940
lymphoma; pharmacogenomic; oxidation; outcomes research
12.  Imaging flow cytometry for automated detection of hypoxia-induced erythrocyte shape change in sickle cell disease 
American journal of hematology  2014;89(6):598-603.
In preclinical and early phase pharmacologic trials in sickle cell disease, the percentage of sickled erythrocytes after deoxygenation, an ex vivo functional sickling assay, has been used as a measure of a patient’s disease outcome. We developed a new sickle imaging flow cytometry assay (SIFCA) and investigated its application. To perform the SIFCA, peripheral blood was diluted, deoxygenated (2% oxygen) for 2 hr, fixed, and analyzed using imaging flow cytometry. We developed a software algorithm that correctly classified investigator tagged “sickled” and “normal” erythrocyte morphology with a sensitivity of 100% and a specificity of 99.1%. The percentage of sickled cells as measured by SIFCA correlated strongly with the percentage of sickle cell anemia blood in experimentally admixed samples (R = 0.98, P ≤ 0.001), negatively with fetal hemoglobin (HbF) levels (R = −0.558, P = 0.027), negatively with pH (R = −0.688, P = 0.026), negatively with pretreatment with the antisickling agent, Aes-103 (5-hydroxymethyl-2-furfural) (R = −0.766, P = 0.002), and positively with the presence of long intracellular fibers as visualized by transmission electron microscopy (R = 0.799, P = 0.002). This study shows proof of principle that the automated, operator-independent SIFCA is associated with predictable physiologic and clinical parameters and is altered by the putative antisickling agent, Aes-103. SIFCA is a new method that may be useful in sickle cell drug development.
PMCID: PMC4180063  PMID: 24585634
13.  Ambulatory Quality Indicators to Prevent Infection in Sickle Cell Disease 
American journal of hematology  2014;89(3):256-260.
The purpose of the present study was to identify rates of adherence for three outpatient quality indicators noted by Wang and colleagues (2011): (1) influenza vaccine, (2) pneumococcal immunizations, and (3) penicillin prophylaxis in patients with sickle cell disease (SCD) in a Medicaid sample. These variables were chosen based on Wang and colleagues’ suggestion that these variables are important for the assessment of the quality of care of children with SCD. We hypothesized that the overall rate of adherence would be poor with adults having worse rates of adherence than children. We conducted a retrospective cohort study using the Wisconsin State Medicaid database over a 5-year period to assess the preventative medication adherence of individuals with SCD. Preventative medication variables in this study included influenza vaccination, pneumococcal immunizations (PCV7, PPV23), and penicillin prophylaxis. As predicted, the 2003 – 2007 Wisconsin State Medicaid database showed patients with SCD had low adherence in terms of recommended influenza vaccinations (21.58% adherent), PPV23 pneumococcal immunizations (43.47% adherent), and penicillin prophylaxis (18.18% adherent). Pneumococcal immunizations for PCV7 were higher than expected (77.27% adherent). Although children tended to adhere to recommended preventative medications more than adults, overall adherence was low. Although we cannot explain why adherence is low, it is likely due to multiple factors at the patient- and provider-level. We encourage patients and providers to create a partnership to meet adherence recommendations, and we describe our strategies for increasing adherence.
PMCID: PMC4450348  PMID: 24779032
quality of life; medication adherence; adults; children; Sickle Cell Disease; Medicaid
14.  Trends and Outcomes of Modern Staging of Solitary Plasmacytoma of Bone 
American journal of hematology  2012;87(7):647-651.
Over the years, the definition of solitary plasmacytoma of bone (SPB) has shifted in part due to more modern testing capabilities. We hypothesized that outcomes data based on antiquated testing would not reflect outcomes using modern staging. To address both how widely applied adequate diagnostic staging is and what the progression rates of SPB as defined with state-of-the-art staging are, we performed a retrospective chart review of those patients with a diagnosis of SPB seen at our institution over the past decade. Two groups were studied: all patients with SPB (n=127); and those patients referred to our institution for an indication other than progression (n=91). The median PFS for those two groups were 26 months and 42 months, respectively. At baseline, only a minority of patients had state-of-the-art staging. The 5 patients with both modern imaging and a negative bone marrow had a 21 month PFS of 100%. Patients with plasmacytoma plus--one plasmacytoma but bone marrow consistent with monoclonal gammopathy of undetermined significance--fair worse than true SPB. The use of modern staging appears to be beneficial in the initial staging of SPB, and there may be a role for PET/CT in future diagnostic work up.
PMCID: PMC4440242  PMID: 22549792
15.  A Phase II Trial of The Oral Mtor Inhibitor Everolimus in Relapsed Hodgkin Lymphoma 
American journal of hematology  2010;85(5):320-324.
Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin Lymphoma (HL). The goal of this trial was to learn the anti-tumor activity and toxicity of everolimus in patients with relapsed/refractory HL.
Patients and Methods
Patients were eligible if they had measurable disease, a platelet count ≥75,000 and an absolute neutrophil count ≥1,000. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Response was assessed after 2 and 6 cycles and then every 3 cycles until progression. Patients could remain on drug until progression or toxicity.
Nineteen patients were enrolled. Median age was 37 years (range, 27-68). Patients had received a median of 6 prior therapies (range, 3-14) and 84% had undergone prior autologous stem cell transplant. The ORR was 47% (95% CI: 24-71%) with 8 patients achieving a PR and 1 patient achieving a CR. The median TTP was 7.2 months. Four responders remained progression free at 12 months. Patients received a median of 7 cycles of therapy. Of the 19 patients, 1 remains on therapy at 36 months; the others went off-study due to progressive disease (16), toxicity (1), and death from infection (1). Four patients experienced a grade three or higher pulmonary toxicity.
Everolimus has single-agent activity in relapsed/refractory HL and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant.
PMCID: PMC4420736  PMID: 20229590
lymphoma; Hodgkin Lymphoma; everolimus; rapamycin; mTOR
16.  Factors Associated with Survival in a Contemporary Adult Sickle Cell Disease Cohort 
American journal of hematology  2014;89(5):530-535.
We examined the relationship of clinical differences among sickle cell disease (SCD) patients in order to understand the major contributors to early mortality in a contemporary cohort.
Survival data were obtained for 542 adult subjects who were enrolled since 2002 at three university hospitals in the southeast United States. Subjects were followed for a median of 9.3 years. At enrollment, clinical parameters were collected, including hemoglobin (Hb) genotype, baseline laboratory values, comorbidities, and medication usage. Levels of soluble adhesion molecules were measured for a subset of 87 subjects. The relationship of clinical characteristics to survival was determined using regression analysis.
Median age at enrollment was 32 years. Median survival was 61 years for all subjects. Median survival for Hb SS and Sβ0 was 58 years and for Hb SC and Sβ+ was 66 years. Elevated white blood count, lower estimated glomerular filtration rate, proteinuria, frequency of pain crises, pulmonary hypertension, cerebrovascular events, seizures, stroke, sVCAM-1 and short-acting narcotics use were significantly associated with decreased survival. 42% of subjects were on hydroxyurea therapy, which was not associated with survival.
SCD continues to reduce life expectancy for affected individuals, particularly those with Hb Sβ0 and SS. Not only were comorbidities individually associated with decreased survival, but an additive effect was observed, so that those with a greater number of negative endpoints had worse survival (p<0.0001). The association of higher sVCAM-1 levels with decreased survival suggests that targeted therapies to reduce endothelial damage and inflammation may also be beneficial.
PMCID: PMC3988218  PMID: 24478166
sickle; anemia; survival; mortality; adhesion; phenotypes
17.  Horse Antithymocyte Globulin as Salvage Therapy after Rabbit Antithymocyte Globulin for Severe Aplastic Anemia 
American journal of hematology  2014;89(5):467-469.
The effectiveness of salvage therapy for aplastic anemia patients unresponsive to initial rabbit antithymocyte globulin (r-ATG) or cyclophosphamide is not known. We investigated standard horse ATG (h-ATG) plus cyclosporine (CsA) in patients who were refractory to initial r-ATG/CsA (n=19) or cyclophosphamide/CsA (n=6) (registered at as NCT00944749). The primary endpoint was hematologic response at 3 months and was defined as no longer meeting criteria for severe aplastic anemia. Of the 19 patients who received r-ATG as initial therapy, 4 (21%) achieved a hematologic response by 3 months, and of the 6 patients who received cyclophosphamide, only 1 (17%) responded at 6 months. Among responders there have been no cases of relapse, and in nonresponders 2 patients evolved to monosomy 7. The overall survival for the cohort at 3 years was 68% (95% CI, 50-91%). These results suggest that only a minority can be successfully salvaged after receiving as first therapy either r-ATG or cyclophosphamide. While h-ATG may be utilized in the salvage setting, the overall response rate likely will be lower than when h-ATG is used as initial treatment.
PMCID: PMC4058301  PMID: 24415649
18.  Hepcidin-dependent and hepcidin-independent regulation of erythropoiesis in a mouse model of anemia of chronic inflammation 
American journal of hematology  2014;89(5):470-479.
Increased hepcidin antimicrobial peptide correlates with hypoferremia and anemia in various disease states, but its requirement for anemia of inflammation has not been adequately demonstrated. Anemia of inflammation is usually described as normocytic and normochromic, while diseases associated with over expression of hepcidin, alone, are often microcytic and hypochromic. These differences in erythrocyte parameters suggest anemia in many inflammatory states may not be fully explained by hepcidin-mediated iron sequestration. We used turpentine-induced sterile abscesses to model chronic inflammation in mice with targeted disruption of Hepcidin 1 [Hepc1 (−/−)] or its positive regulator, lnterleukin-6 [IL-6 (−/−)], to determine whether these genes are required for features characteristic of anemia of inflammation. Although hemoglobin levels did not decline in Hepc1 (−/−) mice with sterile abscesses, erythrocyte numbers were significantly reduced compared to untreated Hepc1 (−/−) mice. In contrast, both hemoglobin concentration and erythrocyte number declined significantly in wild type and IL-6 (−/−) mice with sterile abscesses. Both Hepc1 (−/−) and IL-6 (−/−) mice had increased erythrocyte mean cell volume and mean cell hemoglobin following sterile abscesses, while wild types had no change. Thus, IL-6 (−/−) mice with sterile abscesses exhibit an intermediate phenotype between wild type and Hepc1 (−/−). Our results demonstrate the requirement of Hepc1 for the development of anemia in this rodent model. Simultaneously, our results demonstrate hepcidin-independent effects of inflammation on the suppression of erythropoiesis. Our results suggest chronic anemia associated with inflammation may benefit from interventions protecting erythrocyte number in addition to anti-hepcidin interventions aimed at enhancing iron availability.
PMCID: PMC4200395  PMID: 24415655
19.  BRAF Kinase Domain Mutations are Common in RASwt Chronic Myelomonocytic Leukemia 
American journal of hematology  2014;89(5):499-504.
The frequency of RAS mutations in chronic myelomonocytic leukemia (CMML) suggests that activation of the MAPK pathway is important in CMML pathogenesis. Accordingly, we hypothesized that mutations in other members of the MAPK pathway might be overrepresented in RASwt CMML.
We performed next generation sequencing analysis on 70 CMML patients with known RAS mutation status using the TruSeq Amplicon Cancer Panel kit (Illumina, San Diego, CA).
The study group included 37 men and 33 women with a median age of 67.8 years (range, 28–86 years). Forty patients were RASwt and 30 were RASmut; the latter included KRAS=17; NRAS=12; KRAS+NRAS=1. Next-generation sequencing showed 5 patients (7.1% of total group; 12.5% of RASwt group) with RASwt who had BRAF mutations. All BRAFmut patients had CMML-1; 2 (40%) with MPN-CMML and 3 with MDS-CMML. The BRAF mutations were of missense type and involved exon 11 in 1 patient and exon 15 in 4 patients. All BRAFmut patients had CMML-1 with low-risk cytogenetic findings, and none of the BRAFmut CMML cases were therapy-related. Two (40%) of the 5 patients with BRAFmut patients transformed to acute myeloid leukemia during follow up. Multivariate Cox proportional hazard regression modeling suggests that BRAFmut status is associated with overall survival (p=0.04). Additionally, the RASmut group tended to have worse OS compared to the RASwt group.
In summary, we demonstrate that a subset of patients with RASwt CMML harbors BRAF kinase domain mutations that are potentially capable of activating the MAPK signaling pathway.
PMCID: PMC4207363  PMID: 24446311
chronic myelomonocytic leukemia; next-generation sequencing; BRAF; KRAS; NRAS
20.  Impact of comorbidities by ACE-27 in the revised-IPSS for patients with myelodysplastic syndromes 
American journal of hematology  2014;89(5):509-516.
Comorbidities significantly affect the prognosis and outcomes of patients with hematological malignancies. We have previously reported the impact of comorbidities on the International Prognostic Scoring System (IPSS) score. The aim of this study was to determine whether comorbidities continued to have a significant impact when patients were reclassified according to the Revised-IPSS (IPSS-R). The medical records of 600 consecutive myelodysplastic syndrome patients who presented to MD Anderson Cancer Center between January 2002 and June 2004 were reviewed. The Adult Comorbidity Evaluation-27 (ACE-27) was used to assess the severity of comorbid conditions. Four hundred and two (67%) patients were male. Median age at presentation was 66.6 years (17–94). Mean duration of follow-up was 54 months (1–100). Five hundred and two (84%) patients died, and 54 (9%) patients underwent stem cell transplantation. Overall median survival was 16.8 months (1–100). Median survival by IPSS-R was 47, 34, 21, 16, and 6 months for patients in very low, low, intermediate, high, and very high-risk groups, respectively (P < 0.001). The ACE-27 comorbidity score significantly impacted the median survival of patients in the intermediate (P < 0.001), high (P = 0.045), and very high (P = 0.004) IPSS-R groups; but did not significantly impact the median survival in the low (P = 0.11) and very low (P = 0.49) IPSS-R groups. The ACE-27 comorbidity score significantly impacted the median survival of patients ≤65 years (P < 0.001) but did not significantly impact those >65 years (P = 0.18). Assessment of comorbidity may enhance the prognostic ability of the IPSS-R. Am. J. Hematol. 89:509-516, 2014.
PMCID: PMC4221257  PMID: 24458781
21.  Phase I Study of Oral Clofarabine Consolidation in Adults Aged 60 and Older with Acute Myeloid Leukemia 
American journal of hematology  2014;89(5):487-492.
Clofarabine has shown activity and tolerability in older patients with acute myeloid leukemia (AML). We investigated the safety and tolerability of an oral formulation of clofarabine for consolidation therapy of patients aged 60 and older with AML. In this phase I study, twenty-two patients older than 60 years with AML in first complete remission were treated once daily with oral clofarabine for 14 or 21 days of a 28 day cycle, for up to 5 cycles. Dose escalation from 1 mg to 6 mg daily using a 3 + 3 design was used to determine dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and tolerability of oral clofarabine. No DLTs or Grade 3-4 nonhematologic toxicities were observed. The primary toxicities were hematologic, including uncomplicated grade 3-4 neutropenia (50%) and thrombocytopenia (50%). Given that myelosuppression necessitating dose delays/reductions was observed more commonly at higher doses, the recommended phase II dose is 2 mg daily for 21 of 28 days. At doses equal to or greater than 2 mg, the median relapse-free survival was 28.35 months. Oral clofarabine was well-tolerated with encouraging activity in patients older than 60 years. Further investigation of oral clofarabine as a consolidation and/or maintenance therapy in AML for older individuals is warranted. (
PMCID: PMC4378713  PMID: 24415560
23.  Combination therapy with a Tmprss6 RNAi-therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β-thalassemia intermedia 
American Journal of Hematology  2015;90(4):310-313.
β-thalassemias result from diminished β-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To further interrogate the efficacy of an RNAi-therapeutic downregulating Tmprss6, β-thalassemic Hbbth3/+ animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbbth3/+ animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-thalassemia intermedia. Am. J. Hematol. 90:310–313, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
PMCID: PMC4403964  PMID: 25557851
24.  Prediction of Adverse Events during Intensive Induction Chemotherapy for Acute Myeloid Leukemia or High-Grade Myelodysplastic Syndromes 
American journal of hematology  2014;89(4):423-428.
Intensive chemotherapy for newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with significant treatment-related morbidity and mortality. Herein, we investigate how pre-treatment characteristics relate to early adverse outcomes in such patients. Among 205 consecutive patients, grade 4 neutropenia (i.e. absolute neutrophil count <500/µL) was associated with the development of fever (P=0.0378), documented infection (P<0.0001), bacteremia (P=0.002), delayed neutrophil count recovery (P<0.0001), and death within 35 days of chemotherapy (P=0.04) but not the requirement for intensive care unit-level care. Low monocyte and lymphocyte counts at baseline were similarly associated with increased risk of documented infection or bacteremia. After adjustment for age, gender, disease type, cytogenetic risk, and performance status, the risk of documented infection or bacteremia was 2.51 (95% confidence interval: 1.59–3.96)-fold and 1.82 (1.04–3.19)-fold higher in patients with initial grade 4 neutropenia. There was no significant relationship between adverse events and age, gender, disease type, disease risk, anthracycline type/dose, or initial peripheral blood blast count. Together, our studies identify severe baseline neutropenia as a risk factor for infection-associated adverse events and early death after induction chemotherapy and may provide the rationale for the risk-adapted testing of myeloid growth factor support in this high-risk AML/MDS patient subset.
PMCID: PMC4391649  PMID: 24382796
acute myeloid leukemia (AML); adverse events; chemotherapy-induced neutropenia; febrile neutropenia; induction chemotherapy; myelodysplastic syndrome (MDS)
25.  Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma 
American journal of hematology  2014;89(8):E116-E120.
The combination of clarithromycin, lenalidomide and dexamethasone (BiRd) has led to highly durable responses in newly diagnosed myeloma. However, the ability of clarithromycin to overcome resistance to lenalidomide and dexamethasone (Rd) is not known. To study this, we performed a retrospective analysis of 24 patients with myeloma for which clarithromycin was added to Rd at the time of progression on Rd. The median number of prior therapies was 3 (range 1–8). The best response was complete response (CR) in one (4.2%), very good partial response (VGPR) in one (4.2%) and partial response in eight (33.3%) patients. Ten patients, 41.7% (95% CI: 22.1, 63.4), achieved ≥PR. The median time to response was 4.4 months (range 1–13.6 months) and the median duration of response was 6.9 months (range 3–52.2 months). The clinical benefit rate (CR + VGPR + PR + MR) was 45.8% (95% CI 25.6, 67.2). The median progression-free survival was 4 months. Median overall survival was 25 months with a median follow-up of 27.5 months. The regimen was well tolerated and only 2 patients needed a clarithromycin dose reduction. Addition of clarithromycin to Rd can overcome resistance to Rd in a subset of patients and lead to durable clinical responses.
PMCID: PMC4390045  PMID: 24723438

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