Publications by authors named "Stanley L Schrier"

40 Publications

A reduced transferrin saturation is independently associated with excess morbidity and mortality in older adults with heart failure and incident anemia.

Int J Cardiol 2020 06 12;309:95-99. Epub 2020 Mar 12.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA; Departments of Epidemiology, Biostatistics and Medicine, University of California at San Francisco, San Francisco, CA, USA; Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.

Background: Low transferrin saturation (TSAT) or reduced serum ferritin level are suggestive of iron deficiency but the relationship between iron parameters and outcomes has not been systematically evaluated in older adults with heart failure (HF) and anemia.

Methods: We identified a multicenter cohort of adults age ≥ 65 years with HF and incident anemia (hemoglobin <13 g/dL [men] or < 12 g/dL [women]) between 2005 and 2012. Patients were included if ferritin (ng/mL) and TSAT (%) were evaluated within 90 days of incident anemia. HF hospitalizations and all-cause death were ascertained from electronic health records.

Results: Among 4103 older adults with HF and incident anemia, 47% had TSAT <20% and the median (IQR) ferritin was 126 (53, 256) ng/mL. In multivariable analyses, compared with TSAT ≥20%, patients with TSAT <20% were at increased risk of HF hospitalization for serum ferritin <100 ng/mL (adjusted HR [aHR] 1.40, 95% CI:1.16-1.70) and 100-300 ng/mL (aHR 1.24, 95% CI:1.01-1.52) but not for a ferritin >300 ng/mL (aHR 0.89, 95% CI 0.65-1.23). In addition, TSAT <20% was independently associated with an increased risk of all-cause death regardless of serum ferritin level (<100 ng/mL: aHR 1.42, 95% CI:1.20-1.68; 100-300 ng/mL: aHR 1.18, 95% CI:1.00-1.38; >300 ng/mL: aHR 1.33, 95% CI:1.06-1.69).

Conclusions: Among older adults with HF and incident anemia who had iron studies tested, nearly half had a TSAT <20%, which was independently associated with higher rates of morbidity and death.
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http://dx.doi.org/10.1016/j.ijcard.2020.03.020DOI Listing
June 2020

Organ responses with daratumumab therapy in previously treated AL amyloidosis.

Blood Adv 2020 02;4(3):458-466

Deparment of Medicine, Stanford University School of Medicine, Stanford, CA and.

Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)-free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.
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http://dx.doi.org/10.1182/bloodadvances.2019000776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013253PMC
February 2020

levels in human hematopoietic progenitors are regulated by aging and dictate erythroid-myeloid balance.

Haematologica 2020 04 6;105(4):905-913. Epub 2019 Jun 6.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, USA

Healthy bone marrow progenitors yield a co-ordinated balance of hematopoietic lineages. This balance shifts with aging toward enhanced granulopoiesis with diminished erythropoiesis and lymphopoiesis, changes which likely contribute to the development of bone marrow disorders in the elderly. In this study, RUNX3 was identified as a hematopoietic stem and progenitor cell factor whose levels decline with aging in humans and mice. This decline is exaggerated in hematopoietic stem and progenitor cells from subjects diagnosed with unexplained anemia of the elderly. Hematopoietic stem cells from elderly unexplained anemia patients had diminished erythroid but unaffected granulocytic colony forming potential. Knockdown studies revealed human hematopoietic stem and progenitor cells to be strongly influenced by RUNX3 levels, with modest deficiencies abrogating erythroid differentiation at multiple steps while retaining capacity for granulopoiesis. Transcriptome profiling indicated control by RUNX3 of key erythroid transcription factors, including and These findings thus implicate RUNX3 as a participant in hematopoietic stem and progenitor cell aging, and a key determinant of erythroid-myeloid lineage balance.
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http://dx.doi.org/10.3324/haematol.2018.208918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109730PMC
April 2020

Clinical impact of expression in high-risk acute promyelocytic leukemia.

Blood Adv 2017 Sep 15;1(21):1807-1814. Epub 2017 Sep 15.

Department of Internal Medicine, Medical School of Ribeirao Preto and.

Although overexpression of the brain and acute leukemia, cytoplasmic () gene is associated with primary resistant disease and shorter relapse-free, disease-free, and overall survival in different subsets of acute myeloid leukemia (AML), little is known about its clinical impact in acute promyelocytic leukemia (APL). Using real-time reverse transcriptase polymerase chain reaction, we showed that expression is significantly lower in APL compared with other subsets of AML ( < .001). We also demonstrated that overexpression was associated with shorter disease-free survival (DFS) (hazard ratio [HR], 4.43; 95% confidence interval [CI], 1.29-15.2; = .018) in 221 consecutive patients (median age, 35 years; range, 18-82 years) with newly diagnosed APL homogeneously treated with all- retinoic acid and anthracycline-based chemotherapy. Cox proportional hazard modeling showed that overexpression was independently associated with shorter DFS in the total cohort (HR, 5.26; 95% CI, 1.52-18.2; = .009) and in patients with high-risk disease (ie, those with initial leukocyte counts >10 × 10/L) (HR, 5.3; 95% CI, 1.14-24.5; = .033). We conclude that expression could be useful for refining risk stratification in APL, although this needs to be confirmed in independent cohorts.
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http://dx.doi.org/10.1182/bloodadvances.2017005926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728094PMC
September 2017

Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis.

Blood 2017 08 14;130(7):900-902. Epub 2017 Jun 14.

Department of Medicine, Stanford University School of Medicine, Stanford, CA.

The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.
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http://dx.doi.org/10.1182/blood-2017-01-763599DOI Listing
August 2017

Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial.

JAMA Intern Med 2017 04;177(4):480-490

Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Importance: In one-third of older men with anemia, no recognized cause can be found.

Objective: To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone levels and unexplained anemia would increase their hemoglobin concentration.

Design, Setting, And Participants: A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ≤12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014.

Interventions: Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months.

Main Outcomes And Measures: The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors.

Results: The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline.

Conclusions And Relevance: Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels.

Trial Registration: clinicaltrials.gov Identifier: NCT00799617.
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http://dx.doi.org/10.1001/jamainternmed.2016.9540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433757PMC
April 2017

Age-associated changes in human hematopoietic stem cells.

Semin Hematol 2017 01 20;54(1):39-42. Epub 2016 Oct 20.

Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Stem Cell Research, Stanford University, Stanford, CA; Department of Pathology, Stanford University, Stanford, CA.

Aging has a broad impact on the function of the human hematopoietic system. This review will focus primarily on the effect of aging on the human hematopoietic stem cell (HSC) population. With age, even though human HSCs increase in number, they have decreased self-renewal capacity and reconstitution potential upon transplantation. As a population, human HSCs become more myeloid-biased in their differentiation potential. This is likely due to the human HSC population becoming more clonal with age, selecting for myeloid-biased HSC clones. The HSC clones that come to predominate with age may also contain disease-causing genetic and epigenetic changes that confer an increased risk of developing into an age-associated clonal hematopoietic disease, such as myelodysplastic syndrome, myeloproliferative disorders, or leukemia. The selection of these aged human HSC clones may be in part due to changes in the aging bone marrow microenvironment. While there have been significant advances in the understanding of the effect of aging on mouse hematopoiesis and mouse HSCs, we have comparatively less detailed analyses of the effect of aging on human HSCs. Continued evaluation of human HSCs in the context of aging will be important to determine how applicable the findings in mice and other model organisms are to the human clinical setting.
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http://dx.doi.org/10.1053/j.seminhematol.2016.10.004DOI Listing
January 2017

Renal Toxicity Associated with Salsalate in Elderly Adults with Anemia.

J Am Geriatr Soc 2016 04;64(4):898-9

Hematpoietic Cellular Therapy Program, School of Medicine, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1111/jgs.14065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863444PMC
April 2016

So you know how to treat iron deficiency anemia.

Blood 2015 Oct;126(17):1971

STANFORD UNIVERSITY SCHOOL OF MEDICINE.

In this issue of Blood, Moretti et al provide data that challenge the entrenched oral treatment of iron deficiency anemia. The paper shows how the newer understanding of hepcidin and iron metabolism in general can lead to very practical improvements in the management of iron deficiency anemia, a disorder that may affect as many as 1 billion people.
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http://dx.doi.org/10.1182/blood-2015-09-666511DOI Listing
October 2015

High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia.

Blood 2015 Nov 1;126(20):2302-6. Epub 2015 Oct 1.

Department of Internal Medicine, Medical School of Ribeirao Preto and Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto, Brazil;

The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.
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http://dx.doi.org/10.1182/blood-2015-01-623330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760128PMC
November 2015

A prospective randomized wait list control trial of intravenous iron sucrose in older adults with unexplained anemia and serum ferritin 20-200 ng/mL.

Blood Cells Mol Dis 2014 Dec 25;53(4):221-30. Epub 2014 Jul 25.

Duke University Medical Center, Center for the Study of Aging, Box 3003, Durham, NC 27710, USA. Electronic address:

Anemia is common in older persons and is associated with substantial morbidity and mortality. One third of anemic older adults have unexplained anemia of the elderly (UAE). We carried out a randomized, wait list control trial in outpatients with UAE and serum ferritin levels between 20 and 200 ng/mL. Intravenous iron sucrose was given as a 200-mg weekly dose for 5 weeks either immediately after enrollment (immediate intervention group) or following a 12-week wait list period (wait list control group). The primary outcome measure was changed in 6-minute walk test (6MWT) distances from baseline to 12 weeks between the two groups. Hematologic, physical, cognitive, and quality of life parameters were also assessed. The study was terminated early after 19 subjects enrolled. The distance walked in the 6MWT increased a mean 8.05±55.48 m in the immediate intervention group and decreased a mean 11.45±49.46 m in the wait list control group (p=0.443). The hemoglobin increased a mean 0.39±0.46 g/dL in the immediate intervention group and declined a mean 0.39±0.85 g/dL in the wait list control group (p=0.026). Thus, a subgroup of adults with UAE may respond to intravenous iron. Enrollment of subjects into this type of study remains challenging.
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http://dx.doi.org/10.1016/j.bcmd.2014.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198614PMC
December 2014

Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study.

Ann Hematol 2014 Dec 2;93(12):2001-10. Epub 2014 Jul 2.

Medical School of Ribeirão Preto, Ribeirao Preto, Brazil.

Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITD(positive) patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD(negative) patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.
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http://dx.doi.org/10.1007/s00277-014-2142-9DOI Listing
December 2014

Refractory warm IgM-mediated autoimmune hemolytic anemia associated with Churg-Strauss syndrome responsive to eculizumab and rituximab.

Am J Hematol 2015 Jan 11;90(1):78-81. Epub 2014 Jul 11.

Division of Hematology, Department of Medicine, Stanford University Medical Center, Stanford, California.

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http://dx.doi.org/10.1002/ajh.23791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435183PMC
January 2015

Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study.

Br J Haematol 2014 Aug 3;166(4):540-9. Epub 2014 May 3.

Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; Centre for Cell Based Therapy, University of São Paulo, Ribeirão Preto, Brazil.

The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid-induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline-based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2-year overall survival (OS) (P = 0·005) and 2-year disease-free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2-year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71-30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08-0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49-43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05-0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99-1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.
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http://dx.doi.org/10.1111/bjh.12921DOI Listing
August 2014

Evaluation and management of anemia in the elderly.

Am J Hematol 2014 Jan;89(1):88-96

Department of Pathology and Medicine, Stanford University School of Medicine, Stanford, California; Department of Medicine, Stanford University School of Medicine, Stanford, California; Division of Hematology, Stanford University School of Medicine, Stanford, California.

Anemia is now recognized as a risk factor for a number of adverse outcomes in the elderly, including hospitalization, morbidity, and mortality. What constitutes appropriate evaluation and management for an elderly patient with anemia, and when to initiate a referral to a hematologist, are significant issues. Attempts to identify suggested hemoglobin levels for blood transfusion therapy have been confounded for elderly patients with their co-morbidities. Since no specific recommended hemoglobin threshold has stood the test of time, prudent transfusion practices to maintain hemoglobin thresholds of 9-10 g/dL in the elderly are indicated, unless or until evidence emerges to indicate otherwise.
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http://dx.doi.org/10.1002/ajh.23598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289144PMC
January 2014

Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis.

Heart Rhythm 2014 Jan 10;11(1):158-62. Epub 2013 Oct 10.

Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford University School of Medicine, Stanford, California. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2013.10.026DOI Listing
January 2014

Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement.

Haematologica 2013 Oct 28;98(10):1593-9. Epub 2013 May 28.

Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low-dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met the criteria for Mayo Clinic cardiac stage III disease. Patients received up to nine cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28-day cycle); melphalan 0.18 mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, and 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. The overall survival rate at 1 year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front-line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high-risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. This trial was registered at www.clinicaltrials.gov (NCT00890552).
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http://dx.doi.org/10.3324/haematol.2013.084574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789465PMC
October 2013

Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1.

Blood 2013 May 11;121(19):3925-35, S1-12. Epub 2013 Mar 11.

Department of Molecular Medicine and Medical Biotechnologies, Federico II University of Naples, Naples, Italy.

Autosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents as a compensated hemolytic anemia with macrocytosis and abnormally shaped red blood cells (RBCs). DHSt is part of a pleiotropic syndrome that may also exhibit pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene for pleiotropic DHSt in a large kindred by exome sequencing analysis within the previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1 missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma membranes of RBCs and its messenger RNA, and protein levels increase during in vitro erythroid differentiation of CD34(+) cells. PIEZO1 is also expressed in liver and bone marrow during human and mouse development. We suggest for the first time a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells with the R2456H mutation exhibit increased ion-channel activity. Functional studies of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in ion-channel activity consistent with the altered cation content of DHSt patient red cells. Our findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells.
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http://dx.doi.org/10.1182/blood-2013-02-482489DOI Listing
May 2013

The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis.

Br J Haematol 2013 May 23;161(3):367-72. Epub 2013 Feb 23.

Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA.

The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.
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http://dx.doi.org/10.1111/bjh.12269DOI Listing
May 2013

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes.

Proc Natl Acad Sci U S A 2013 Feb 6;110(8):3011-6. Epub 2013 Feb 6.

Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine, and Department of Pathology, Stanford University, Stanford, CA 94305, USA.

Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the "don't eat me" signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia.
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http://dx.doi.org/10.1073/pnas.1222861110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581956PMC
February 2013

Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL.

Blood 2013 Mar 14;121(11):1935-43. Epub 2013 Jan 14.

Hematology/Oncology Division, Department of Internal Medicine, Medical School of Ribeirão Preto and Center for Cell Based Therapy, University of São Paulo, Ribeirão Preto, Brazil.

Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries.
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http://dx.doi.org/10.1182/blood-2012-08-449918DOI Listing
March 2013

What does the spleen see?

Blood 2012 Jul;120(2):242-3

Stanford University School of Medicine.

In this issue of Blood, Safeukui et al have come to grips with an important issue in red blood cell (RBC) biology.1 Their study deals not only with the mechanism of RBC removal in diseases like hereditary spherocytosis (HS) and autoimmune hemolytic anemia, but also with RBC senescence.
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http://dx.doi.org/10.1182/blood-2012-05-425991DOI Listing
July 2012

Anemia in the elderly.

Curr Opin Hematol 2012 May;19(3):133-40

Department of Medicine, Stanford University, Stanford, California 94305, USA.

Purpose Of Review: There have been several large-scale epidemiologic studies, including the National Health and Nutrition Examination Survey III (NHANES III), which have described the prevalence and impact of anemia in the elderly. The information derived has been critically important. However, given the large number of patients surveyed, these reports necessarily relied substantially on the laboratory-based screening evaluations. There are now two recent reports describing the cause of anemia in elderly outpatients, and although the numbers are smaller than the large scale surveys, they constitute comprehensive hematologic evaluations with therapeutic interventions and clinical follow-up. The purpose of this review is to compare these different analyses.

Recent Findings: There are distinct differences and similarities in the two types of studies, which are derived from patients seen in hematology clinics. Despite comprehensive hematologic evaluation, the puzzling entity of unexplained anemia of the elderly is confirmed and found to account for 30-46% of patients. NHANES III classified iron-deficiency anemia with other nutritional anemias, a classification that might be correct in the developing third world, but in North America and Western Europe, iron deficiency is more often caused by blood loss and the cause must be sought and dealt with. The myelodysplastic syndromes are an important cause of anemia in the elderly, with a prevalence of at least 4%.

Summary: Large-scale screening studies of anemia in the elderly are of great importance, and when complemented by comprehensive hematologic evaluations, provide a more accurate picture of the clinical situation.
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http://dx.doi.org/10.1097/MOH.0b013e3283522471DOI Listing
May 2012

Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age.

Proc Natl Acad Sci U S A 2011 Dec 28;108(50):20012-7. Epub 2011 Nov 28.

Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Stem Cell Research, and Department of Pathology, Stanford University, Stanford, CA 94305, USA.

In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.
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http://dx.doi.org/10.1073/pnas.1116110108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250139PMC
December 2011

Heart transplantation and cardiac amyloidosis: approach to screening and novel management strategies.

J Heart Lung Transplant 2012 Mar 3;31(3):325-31. Epub 2011 Nov 3.

Department of Internal Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Limited data exist regarding screening methods and outcomes for orthotopic heart transplantation (OHT) in cardiac amyloidosis. As a result, uncertainty exists over the best approach to OHT for cardiac amyloidosis and for the timing of critical post-transplant therapies. This article reviews 6 patients who underwent OHT for cardiac amyloidosis at the Stanford University Amyloid Center from 2008 to present. All patients with light-chain amyloidosis received chemotherapy in the interval between OHT and autologous hematopoietic stem cell transplant. Five patients remain alive up to 25 months after OHT, without evidence of recurrent cardiac amyloid deposition. A novel strategy of OHT, followed by light-chain suppressive chemotherapy before autologous hematopoietic stem cell transplant, is feasible for patients with light-chain amyloidosis.
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http://dx.doi.org/10.1016/j.healun.2011.09.010DOI Listing
March 2012

Molecular basis of two novel mutations found in type I methemoglobinemia.

Blood Cells Mol Dis 2011 Apr 24;46(4):277-81. Epub 2011 Feb 24.

Internal Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, 84132, USA.

Congenital methemoglobinemia due to NADH-cytochrome b5 reductase 3 (CYB5R3) deficiency is an autosomal recessive disorder that occurs sporadically worldwide, although endemic clusters of this disorder have been identified in certain ethnic groups. It is present as two distinct phenotypes, type I and type II. Type I methemoglobinemia is characterized by CYB5R3 enzyme deficiency restricted to erythrocytes and is associated with benign cyanosis. The less frequent type II methemoglobinemia is associated with generalized CYB5R3 deficiency affecting all cells and is lethal in early infancy. Here we describe the molecular basis of type I methemoglobinemia due to CYB5R3 deficiency in four patients from three distinct ethnic backgrounds, Asian Indian, Mexican and Greek. The CYB5R3 gene of three probands with type I methemoglobinemia and their relatives were sequenced revealing several putative causative mutations; in one subject multiple mutations were present. Two novel mutations, S54R and F157C, were identified and the previously described A179T, V253M mutations were also identified. All these point mutations mapped to the NADH binding domain and or the FAD binding domain. Each has the potential to sterically hinder cofactor binding causing instability of the CYB5R3 protein. Wild-type CYB5R3, as well as two of these novel mutations, S54R and F157C, was amplified, cloned, and purified recombinant peptide obtained. Kinetic and thermodynamic studies of these proteins show that the above mutations lead to decreased thermal stability.
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http://dx.doi.org/10.1016/j.bcmd.2011.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075332PMC
April 2011

Anemia in older persons: etiology and evaluation.

Blood Cells Mol Dis 2011 Feb 3;46(2):159-65. Epub 2011 Jan 3.

Department of Medicine (Hematology), Stanford University, Stanford, CA, USA.

The aim of this study was to prospectively determine the etiology of anemia in a cohort of community-dwelling older outpatients with a comprehensive hematologic evaluation. Participants were men and women age 65 and older with anemia as defined by World Health Organization criteria recruited from outpatient hematology clinics at Stanford Hospital and Clinics (SHC) and Veterans Affairs Palo Alto Health Care System (VAPAHCS). Each participant underwent a history and physical examination, followed by a comprehensive hematologic evaluation, which in all participants included complete blood count, red cell indices, review of the blood smear, and assessment of vitamin B12, folate, iron status and renal function. Additional evaluation was obtained by clinical providers as per their discretion. 190 participants enrolled and completed the evaluation. Twelve percent of participants had iron deficiency anemia. Of those with iron deficiency in whom there was follow-up information, half normalized their hemoglobin in response to iron repletion, and half did not. Thirty-five percent of participants had unexplained anemia. Those with unexplained anemia had mildly increased inflammatory markers compared to non-anemic controls, and, at the lower hemoglobin ranges had relatively low erythropoietin levels. Sixteen percent of participants were categorized as being "suspicious for myelodysplastic syndrome." Thus, even with comprehensive hematologic evaluation, unexplained anemia is common in older anemic outpatients. Iron deficiency anemia is also common and can be difficult to diagnose, and frequently the anemia is not fully corrected with iron repletion.
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http://dx.doi.org/10.1016/j.bcmd.2010.11.004DOI Listing
February 2011

To be old is to be inflamed?

Blood 2010 May;115(18):3651-2

Stanford University, USA.

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http://dx.doi.org/10.1182/blood-2010-02-267294DOI Listing
May 2010

Unexplained aspects of anemia of inflammation.

Adv Hematol 2010 24;2010:508739. Epub 2010 Mar 24.

Department of Medicine (Hematology), Stanford University, Stanford, CA 94305-3434, USA.

Anemia of inflammation (AI), also known as anemia of chronic inflammation or anemia of chronic disease was described over 50 years ago as anemia in association with clinically overt inflammatory disease, and the findings of low plasma iron, decreased bone marrow sideroblasts and increased reticuloendothelial iron. Pathogenic features underlying AI include a mild shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the marrow to erythropoietin, and impaired iron metabolism mediated by inflammatory cytokines and the iron regulatory peptide, hepcidin. Despite marked recent advances in understanding AI, gaps remain, including understanding of the pathogenesis of AI associated with "noninflammatory" or mildly inflammatory diseases, the challenge of excluding iron deficiency anemia in the context of concomitant inflammation, and understanding more precisely the contributory role of hepcidin in the development of AI in human inflammatory diseases.
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http://dx.doi.org/10.1155/2010/508739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846342PMC
July 2011

Anemia in the elderly: introduction.

Semin Hematol 2008 Oct;45(4):207-9

Department of Medicine (Hematology), Stanford University, Stanford, CA, USA.

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http://dx.doi.org/10.1053/j.seminhematol.2008.07.001DOI Listing
October 2008