Publications by authors named "Dawn Sheppard"

12 Publications

  • Page 1 of 1

Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation.

JAMA Neurol 2016 06;73(6):652-8

Division of Hematology, University of Ottawa, Ottawa, Ontario, Canada2The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada3The Bone Marrow Transplant Programme, University of Ottawa, The Ottawa Hospital, Ottawa, Ontario, Canada.

Importance: Some patients with myasthenia gravis (MG) do not respond to conventional treatment and have severe or life-threatening symptoms. Alternate and emerging therapies have not yet proved consistently or durably effective. Autologous hematopoietic stem cell transplant (HSCT) has been effective in treating other severe autoimmune neurologic conditions and may have similar application in MG.

Objective: To report 7 cases of severe MG treated with autologous HSCT in which consistent, durable, symptom-free, and treatment-free remission was achieved.

Design, Setting, And Participants: This retrospective cohort study reports outcomes at The Ottawa Hospital, a large, Canadian, tertiary care referral center with expertise in neurology and HSCT, from January 1, 2001, through December 31, 2014, with a median follow-up of 40 months (range, 29-149 months). Data collection and analysis were performed from February 1 through August 31, 2015. All patients with MG treated with autologous HSCT at The Ottawa Hospital were included. All had persistent severe or life-threatening MG-related symptoms despite continued use of intensive immunosuppressive therapies.

Interventions: Autologous hematopoietic stem cell grafts were mobilized with cyclophosphamide and granulocyte colony-stimulating factor, collected by peripheral blood leukapheresis, and purified away from contaminating lymphocytes using CD34 immunomagnetic selection. Patients were treated with intensive conditioning chemotherapy regimens to destroy the autoreactive immune system followed by graft reinfusion for blood and immune reconstitution.

Main Outcomes And Measures: The primary outcome was MG disease activity after autologous HSCT measured by frequency of emergency department visits and hospitalizations and Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA therapy status, and MGFA postintervention status. Safety outcomes included all severe autologous HSCT-related complications.

Results: Seven patients underwent autologous HSCT, 6 for MG and 1 for follicular lymphoma with coincident active MG. Mean (SD) ages at MG diagnosis and at autologous HSCT were 37 (11) and 44 (10) years, respectively. Five patients (71%) had concurrent autoimmune or lymphoproliferative illnesses related to immune dysregulation. All patients had distinct clinical and electromyographic evidence of MG (MGFA clinical classification IIIb-V). All patients achieved durable MGFA complete stable remission with no residual MG symptoms and freedom from any ongoing MG therapy (MGFA postintervention status of complete stable remission). Three patients (43%) experienced transient viral reactivations, and 1 (14%) developed a secondary autoimmune disease after autologous HSCT, all of which resolved or stabilized with treatment. There were no treatment- or MG-related deaths.

Conclusions And Relevance: Autologous HSCT results in long-term symptom- and treatment-free remission in patients with severe MG. The application of autologous HSCT for this and other autoimmune neurologic conditions warrants prospective study.
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http://dx.doi.org/10.1001/jamaneurol.2016.0113DOI Listing
June 2016

Improved Prediction of CD34+ Cell Yield before Peripheral Blood Hematopoietic Progenitor Cell Collection Using a Modified Target Value-Tailored Approach.

Biol Blood Marrow Transplant 2016 Apr 28;22(4):763-767. Epub 2015 Nov 28.

Ottawa Hospital Research Institute, Ottawa, Canada.

The most commonly used stem cell source for both autologous and allogeneic transplantation is mobilized peripheral blood hematopoietic progenitor cells collected by apheresis. In the 1990s, an Italian group used the correlation between the preapheresis peripheral blood CD34+ cell count and the final number of CD34+ cells collected to devise a formula for "target value-tailored" (TVT) apheresis. Using local patient data, the Canadian Blood Services Stem Cell Laboratory created a similar model to determine the blood volume to process during apheresis collection. The objectives of this study were to determine the correlation between the number of CD34+ cells predicted by the TVT formula and the actual number of CD34+ cells collected and to determine whether the TVT formula remains predictive when applied to an external data set. All apheresis collections performed at the Ottawa Hospital between January 1, 2003 and October 2, 2013 were reviewed. The primary outcome was the correlation between the number of CD34+ cells predicted by the TVT formula and the actual number of CD34+ cells collected on day 1 of apheresis. For the external data set, all autologous collections performed at the London Health Sciences Centre between December 1, 2008 and December 1, 2013 were reviewed. The external data set was divided into test and validation sets to determine whether a model could be created to predict the final number of CD34+ cells collected on day 1 based on the preapheresis CD34+ count. A total of 1252 collections were included in the analysis. The Ottawa data set included 1012 collections, 836 of which were autologous and 176 of which were from donors. Of the autologous collections in Ottawa, 764 (92.5%) were first collections. In 759 (91%) collections, chemotherapy plus granulocyte colony-stimulating factor (G-CSF) was used as the mobilization regimen. In 747 collections (89%), only 1 collection day was required to achieve the desired number of CD34+ cells. The TVT estimate was highly predictive of the number of CD34+ cells × 10(6)/kg actually collected on apheresis day 1 (r = .90, P < .0001). The London data set included 240 autologous collections. All mobilizations were with G-CSF alone. For the test set, the precollection CD34+ count was highly predictive of the number of CD34+ cells × 10(6)/kg collected on day 1 of apheresis. Applying this model to the validation set, the correlation between the predicted and final and day 1 CD34+ cells × 10(6)/kg count was .9186 (P < .0001). Using a modified TVT approach, the preapheresis CD34+ count can be used to accurately predict the number of CD34+ cells × 10(6)/kg collected on day 1. This approach can be applied at other centers and for different diseases and mobilization regimens. This method can be used to individualize the blood volume processed and, thus, optimize resource utilization.
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http://dx.doi.org/10.1016/j.bbmt.2015.11.016DOI Listing
April 2016

Haematological problems in obstetrics.

Best Pract Res Clin Obstet Gynaecol 2015 Jul 4;29(5):671-84. Epub 2015 Mar 4.

Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Canada; Ottawa Blood Disease Centre, The Ottawa Hospital, Ottawa, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada; Canadian Blood Services, Ottawa, Canada. Electronic address:

Physiologic changes occur during pregnancy, which influence normal haematologic values and impact the diagnosis and management of haematologic disease in pregnancy. Physiologic changes of pregnancy also commonly lead to mimicking symptoms of haematologic disease that may prompt investigations for haematologic disease. The toxicity and radiation associated with the diagnostic imaging and pharmacologic management of both benign and malignant haematological conditions during pregnancy present unique challenges. Strategies for diagnosis and treatment must weigh the benefits and risks to the mother while also taking foetal outcome into consideration. In this review, we highlight the common haematologic diseases encountered by obstetricians and try to provide guidance for the most prevalent diagnostic and therapeutic questions. At the other end of the spectrum, we also comment on less common but very challenging haematologic diseases in pregnancy that require multidisciplinary effort to arrive at difficult individual diagnostic and treatment decisions.
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http://dx.doi.org/10.1016/j.bpobgyn.2015.02.004DOI Listing
July 2015

Current trends in clinical studies of allogeneic hematopoietic stem cell transplantation.

Biol Blood Marrow Transplant 2015 Feb 19;21(2):364-70. Epub 2014 Oct 19.

Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address:

Allogeneic hematopoietic stem cell transplantation (HSCT) is a specialized intervention performed at select centers worldwide. The extent to which specific aspects of care in allogeneic HSCT have been studied and the types of studies performed for different aspects of care remains incompletely documented. Studies in allogeneic HSCT were systematically identified from selected high-profile transplant journals between July 2010 and June 2011 and previously reported in a study addressing the definition of clinical outcomes in HSCT. All articles were retrieved and assessed for study characteristics and categorized by specific aspects of care related to allogeneic HSCT. One hundred sixteen articles were retrieved and reviewed in detail by 2 investigators. The most studied aspect of care was conditioning regimens. Transfusion practices were the most understudied aspect of care. Interestingly, most studies included both adult and pediatric patients. Studies involving all hematological malignancies were encountered more often than disease-specific studies. Geographically, most patients described in the published reports were treated only in North America or only in Europe. Most studies were retrospective (78), and 25 reported on multicenter registry data. Of the 38 prospective studies, 8 were randomized controlled trials (RCTs) and predominantly focused on prevention and treatment of graft-versus-host disease (GVHD) and infections. Median follow-up was longer in retrospective registry studies (54 months) and shortest in RCTs (32 months). The proportion of positive outcomes in retrospective and prospective studies was remarkably high (>80% for all categories) and not significantly different across all aspects of care (P > .05). When comparing RCTs and registry data studies, this proportion was similar and high (95% and 100%, respectively, P > .05). Our study highlights the established and important role of retrospective registry studies for many aspects of care and suggests RCTs may be most relevant for studies on infectious complications and GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2014.09.014DOI Listing
February 2015

Autologous stem cell transplantation for stiff person syndrome: two cases from the Ottawa blood and marrow transplant program.

JAMA Neurol 2014 Oct;71(10):1296-9

Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, Ontario, Canada3Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Importance: Stiff person syndrome (SPS) is a rare neurological disease causing significant functional disability for patients and presenting a therapeutic challenge for clinicians. Autologous hematopoietic stem cell transplantation (auto-HSCT) has been used successfully to remit autoimmune-mediated neurological diseases. We report 2 cases of severe SPS treated with auto-HSCT, a novel therapy for this disease.

Observations: Two anti-glutamic acid decarboxylase antibody-positive patients with SPS had an autologous hematopoietic stem cell graft collected and stored. Subsequently, the patients underwent auto-HSCT. Both patients achieved clinical remission with sustained, marked improvement in symptoms and a return to premorbid functioning, now more than 2.5 and 4.5 years after the procedure.

Conclusions And Relevance: Stiff person syndrome represents a novel indication for auto-HSCT. The resolution of clinical manifestations of SPS despite the persistence of anti-glutamic acid decarboxylase antibodies following auto-HSCT suggests that the antibody does not play a direct role in pathogenesis of SPS.
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http://dx.doi.org/10.1001/jamaneurol.2014.1297DOI Listing
October 2014

Impact of platelet transfusion on toxicity and mortality after hematopoietic progenitor cell transplantation.

Transfusion 2015 Feb 15;55(2):253-8. Epub 2014 Aug 15.

Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Background: Thrombocytopenia occurs commonly after hematopoietic progenitor cell transplantation (HPCT) and is associated with potential morbidity and mortality. Few studies have examined the impact of platelet (PLT) transfusion on clinical outcomes in HPCT while optimal PLT transfusion strategies after HSCT remain uncertain.

Study Design And Methods: A retrospective single-center cohort study was conducted on 522 patients undergoing HPCT between January 2002 and December 2007. Associations between PLT transfusion events and clinical characteristics with transplant-related outcomes were assessed using univariate and multivariate analysis.

Results: Mean number of PLT transfusion events before Day +60 posttransplant was 7.5 (95% confidence interval, 6.7-8.4) with greater number of events after allogeneic compared with autologous HPCT (p < 0.01). Univariate and multivariate analysis confirmed that the number of PLT transfusion events was associated with increased 100-day nonrelapse mortality (p < 0.01), posttransplant length of hospital stay (p < 0.01), need for intensive care unit admission (p < 0.01), and number of organs affected by severe toxicity (p < 0.01).

Conclusion: HPCT-related toxicity and mortality are associated with increased PLT transfusion events. Alternative strategies to reduce PLT transfusions after HPCT may warrant future study.
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http://dx.doi.org/10.1111/trf.12817DOI Listing
February 2015

Systemic mastocytosis emerging after azacitidine treatment of refractory anaemia with excess blasts type 2.

Br J Haematol 2014 Oct 9;167(2):147. Epub 2014 Jul 9.

Division of Haematopathology and Transfusion Medicine, Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, Canada.

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http://dx.doi.org/10.1111/bjh.13024DOI Listing
October 2014

A single-institution analysis of the utility of pre-induction ejection fraction measurement in patients newly diagnosed with acute myeloid leukemia.

Leuk Lymphoma 2015 Jan 17;56(1):135-40. Epub 2014 Jul 17.

The Ottawa Hospital and Department of Medicine, University of Ottawa , Ottawa, ON , Canada.

Anthracyclines, a standard component of induction therapy for acute myeloid leukemia (AML) are known to be cardiotoxic. Existing evidence supporting routine baseline pre-induction cardiac function testing is limited. We conducted a retrospective analysis of 119 consecutive patients diagnosed with AML at our center from 2009 to 2012. In the 76 patients for whom induction chemotherapy was planned, baseline ejection fraction measurements were rarely abnormal (four cases), and in none of these abnormal cases did the result change management decisions. Awaiting LVEF evaluation results led to a delay in chemotherapy administration by a mean of approximately 2 days at significant additional costs to the healthcare system. Routine baseline ejection fraction measurement should be abandoned as it does not change management, results in treatment delay and unnecessary healthcare expenditures. More selective baseline testing, preferentially in patients in whom there is a clinical reason of cardiac disease, should be pursued.
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http://dx.doi.org/10.3109/10428194.2014.883072DOI Listing
January 2015

A case of erythrocytosis in a patient treated with an aromatase inhibitor for breast cancer.

Case Rep Hematol 2013 7;2013:615189. Epub 2013 Nov 7.

Hematology Division, Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6.

A previously healthy 79-year-old female was referred to hematology for further evaluation of erythrocytosis. Two years earlier she had been diagnosed with ER/PR-positive ductal carcinoma of the breast and was receiving hormonal therapy with exemestane. No secondary cause of erythrocytosis was identified. Serum erythropoietin (EPO) level was normal, and molecular testing for the JAK2 V617F and exon 12 mutations was negative. A bone marrow biopsy showed a mild increase in erythropoiesis, and no spontaneous erythroid colonies were demonstrated. Erythrocytosis is common reason for referral to a hematologist. The myeloproliferative disorder, polycythemia vera, and the rare congenital polycythemias represent primary erythrocytosis. Common secondary causes include smoking, obstructive sleep apnea, and other pulmonary diseases. Erythrocytosis is well described with certain classes of drugs, including androgens. We hypothesize that exemestane contributed to the development of erythrocytosis in our patient. To our knowledge, erythrocytosis has not been previously described in association with aromatase inhibitors. These drugs prevent the conversion of androstenedione and testosterone to estrogen; thus the physiologic mechanisms may be similar to those responsible for erythrocytosis seen with exogenous androgens. These mechanisms are not well understood, but may include altered iron metabolism by a reduction in hepcidin levels.
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http://dx.doi.org/10.1155/2013/615189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838821PMC
December 2013

What is the optimal approach to major ABO-incompatible allogeneic stem cell transplantation?

Biol Blood Marrow Transplant 2013 Dec 8;19(12):1760. Epub 2013 Oct 8.

Department of Haematology, The Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.bbmt.2013.09.019DOI Listing
December 2013

Is cytomegalovirus testing of blood products still needed for hematopoietic stem cell transplant recipients in the era of universal leukoreduction?

Biol Blood Marrow Transplant 2013 Dec 5;19(12):1719-24. Epub 2013 Oct 5.

Division of Hematology, Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.

Hematopoietic stem cell transplantation (HSCT) recipients are a high-risk, immunocompromised group of patients who receive frequent transfusions after transplantation. Transfusion of cytomegalovirus (CMV)-negative blood products has long been the standard of care to prevent transfusion-transmitted CMV in this patient population. Leukoreduction of blood products before transfusion has been shown to significantly reduce the risk of transfusion-transmitted CMV. In the era of universal leukoreduction in Canada, the need for CMV testing of blood products remains unclear. We sought to identify whether there is a difference in transfusion-transmitted CMV viremia in patients receiving only leukoreduced versus CMV-negative and leukoreduced blood products in HSCT recipients. Patients who were CMV negative and received an allogeneic HSCT from a CMV-negative donor between October 1, 1999 and June 30, 2012 were included in the analysis. Transfusion data were collected from The Ottawa Hospital Blood Bank and Canadian Blood Services. CMV viremia was defined as PCR positivity. One hundred sixty-six patients were identified who met the inclusion criteria. Of these, 89 patients received an HSCT before January 2007, during the time when patients received leukoreduced and CMV-negative blood products. Seventy-seven patients received an HSCT after this time, receiving only leukoreduced blood products. The 2 groups did not differ in terms of age, gender, diagnosis, graft type, graft source, conditioning regimen, or ABO compatibility (P > .05). CMV viremia was detected in 3 patients who received CMV-negative leukoreduced blood products (3.37%) and in 1 patient who received only leukoreduced blood products (1.30%, P = .6244). Of the patients who developed CMV viremia, 2 developed suspected CMV disease. Both of these patients were transfused with CMV-negative blood products. Secondary outcomes, including total length of stay in hospital, admission to the intensive care unit, acute and chronic graft versus host disease, and 100-day nonrelapse mortality, did not differ between the groups. In the era of universal leukoreduction of blood products, this study demonstrates that testing for CMV-negative blood products is not needed for HSCT recipients.
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http://dx.doi.org/10.1016/j.bbmt.2013.09.013DOI Listing
December 2013

Systematic review of randomized controlled trials of hematopoietic stem cell mobilization strategies for autologous transplantation for hematologic malignancies.

Biol Blood Marrow Transplant 2012 Aug 16;18(8):1191-203. Epub 2012 Jan 16.

Ottawa Hospital Blood and Marrow Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada.

Collection of adequate hematopoietic stem cells (HSCs) is necessary for successful autologous transplantation; however, a proportion of patients fail to collect the minimum number of cells required. We summarized the efficacy and safety of HSC mobilization strategies. We performed a systematic review of randomized controlled trials comparing HSC mobilization strategies before autologous transplantation for hematologic malignancies. The primary outcome was CD34+ cell yield. Secondary outcomes included number of aphereses, proportion of failures, rate of count recovery, and adverse events. We identified 28 articles within 3 broad strategies. Using a cyclophosphamide with growth factor strategy (10 articles), CD34+ cell yield is improved by addition of molgramostim to cyclophosphamide (1.4 vs 0.5 × 10(6)/kg; P = .0165), addition of cyclophosphamide to filgrastim (7.2 vs 2.5 × 10(6)/kg; P = .004), and addition of ancestim to cyclophosphamide and filgrastim (12.4 vs 8.3 × 10(6)/kg; P = .007). Within a growth factor-based strategy (6 articles), addition of plerixafor improves CD34+ cell yield over filgrastim alone in multiple myeloma (MM; 11.0 vs 6.2 × 10(6)/kg; P < .001) and non-Hodgkin lymphoma (5.69 vs 1.98 × 10(6)/kg; P < .01). With combination or noncyclophosphamide-based chemotherapy (12 articles), higher-dose filgrastim (8.2 vs 4.7 × 10(6)/kg for 16 vs 8/mcg/kg daily of filgrastim, respectively; P < .0001) and addition of rituximab to etoposide and filgrastim (9.9 vs 5.6 × 10(6)/kg; P = .021) improve CD34+ cell yield. Growth factor alone after chemotherapy, ancestim, or plerixafor provide adequate autologous HSC grafts for the majority of patients. Although some strategies result in higher CD34+ cell yield, this potentially comes at the expense of increased toxicity. As all strategies are reasonable, programmatic, and patient-specific considerations must inform the approach to autologous graft mobilization.
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http://dx.doi.org/10.1016/j.bbmt.2012.01.008DOI Listing
August 2012
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