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Overview

The vision of Providence Hematology is “Excellence in Care, Teaching and Research for Blood Disorders and Blood Cancers”.  Though these goals are intricately interrelated, here we describe hematology research.

LEADS

Dr. Heather Leitch, MD, PhD, Director, Hematology/Oncology Research at Providence Health Care; Clinical Professor of Medicine, UBC

Dr. Lynda Foltz, MD, Head, Division of Hematology at Providence Health Care; Clinical Associate Professor of Medicine, UBC

OTHER INVESTIGATORS

Hematologists: Dr. Chantal Leger; Dr. Khaled Ramadan; Dr. Hatoon Ezzat; Dr. Shannon Jackson; Dr. Camilla Ross

Research Staff: Rachel Despotovic, Research Manager; Gail Vicente, Senior Study Coordinator; Alexia Silva, Research Associate

INTRODUCTION

The physicians and staff in the Division of Hematology at St. Paul’s Hospital are committed to improving the care of patients with blood disorders and blood cancers by improving knowledge about these conditions and about new treatments for them.  To achieve this, Hematology Research studies all aspects of blood disorders and blood cancers.  Many of the efforts of the St. Paul’s Hematology Research group have been successful in achieving these goals.  For example, the group has taken a leadership role in research aimed at improving the understanding and treatment of patients with acquired anemias such as MDS requiring transfusion, which can lead to the accumulation of (toxic) iron in the organs.

 

Myelodysplastic Syndromes.  Image from: Robbins SL, Cotran RS.
Pathologic basis of disease. 7th ed. St Louis, MO: WB Saunders; 2004.

 

VISIONARY RESEARCH AT PROVIDENCE HEMATOLOGY

The myelodysplastic syndromes (MDS) are a group of bone marrow disorders characterized low blood cell counts and an increased risk of developing acute myelogenous leukemia (AML); AML can develop over time in up to one-third of MDS patients.   In the past, MDS was classified as a disease of low malignant potential and referred to as a pre-leukemia. Now that more has been learned about MDS, it is considered to be a form of cancer. The incidence of MDS, like many bone marrow cancers, is increasing, which is partially related to the aging population of Canada, particularly in British Columbia.  You can read more about MDS at: http://www.cancer.ca/en/cancer-information/cancer-type/leukemia/leukemia/myelodysplastic-syndromes/?region=on#ixzz3zhL34VKJ


Every unit of RBC contains 200 to 250mg of iron in hemoglobin, which transports oxygen to the tissues, and the body has no mechanism to excrete excess iron, which can accumulate in the  organs and result in: scarring of the liver and liver cancer; heart failure and abnormal heart rhythms; and diabetes; and can also worsen bone marrow failure, and possibly accelerate progression to AML.Most patients with MDS eventually develop a requirement for regular red blood cell (RBC) transfusions to partially correct progressive anemia and support life.  RBC transfusion dependence is associated with shortened survival and reduced quality of life.  The increasing number of patients who are RBC transfusion dependent put an increasing strain on health care resources, such as infusion times in the Medical Short Stay Unit at St. Paul’s Hospital.

St. Paul’s Hospital has taken a global leadership position into alerting hematologists to the harmful effects of transfusional iron overload and the importance of minimizing and reversing these effects through the use of iron chelation therapy in patients with MDS and other bone marrow failure syndromes.  This has been done through clinical trials and also retrospective studies, and our findings have been shared worldwide through lecture tours, review articles and editorials, inclusion in think tanks and the development of new clinical trials, the development of web-based therapeutic algorithms (www.MDSClearPath.org), and inclusion in the educational resources of the American Society of Hematology (ASH).

 

 

 

 

Iron overload accumulates in tissues and organs, causing cellular damage, organ dysfunction and organ failure.  These effects can be reversed by reducing iron overload with iron chelation therapy.

 

Similar initiatives have been taken in other blood cancers including chronic lymphocytic leukemia (CLL); myeloproliferative neoplasms (MPN) such as primary myelofibrosis (PMF) and others; HIV-related lymphoma; and more.  Other studies focus on non-malignant blood disorders such as: bleeding disorders; hereditary anemias; non-malignant blood conditions in persons living with HIV; and more.Other research in MDS includes groundbreaking descriptions of autoimmune manifestations of MDS, and treatment of higher risk MDS in patients living with well controlled HIV infection (read more at: Williamson BT, Foltz LM and Leitch HA.  Autoimmune Manifestations Presenting within Myelodysplastic Syndromes: a Case Series and Literature Review. Canadian Conference on MDS, Banff, September 12-13 2014, www.ccmds-banff.ca/   and Williamson BT and Leitch HA, “Higher Risk Myelodysplastic Syndromes in Patients with Well-Controlled HIV Infection: Clinical Features, Treatment, and Outcome,” Case Reports in Hematology, vol. 2016, Article ID 8502641, 7 pages, 2016. doi:10.1155/2016/8502641.).

CURRENT CLINICAL TRIALS

MDS Quality of Life (QOL) in Canada: A national prospective study of the epidemiology, QOL and impact of comorbidity/frailty on MDS outcome.  This study enrolls patients from across Canada onto a national MDS registry.  It examines QOL through 6 monthly questionnaires and yearly small tests of physical function.  Goals are to determine the impact of measures of QOL on MDS outcome, but also to determine the impact of MDS treatments on QOL.  Dr. Heather Leitch is the Principal Investigator for this study at St. Paul’s, and all St. Paul’s hematologists participate.

A phase II, randomized, pilot study to assess the effect in terms of erythroid improvement of deferasirox (an iron chelator which can itself cause blood counts to improve) combined with erythropoietin compared to erythropoietin alone in patients with lower risk myelodysplastic syndrome.  Led by Dr. Heather Leitch; currently closed to enrollment.

BioLym study – Non-Hodgkin lymphoma, Hodgkin lymphoma, myeloma and lymphocytic leukemia are called lymphoid cancers because they originate in white blood cells called lymphocytes. These cancers are the fourth most common cancer type in Canada and their frequency is rising each year. Research to determine how these cancers begin, what causes them, how to treat them and the long term effects of treatments is needed. The study asks patients to donate a blood sample and give consent to have their diagnostic tissue biopsy studies by researchers to help to understand better how to treat these cancers.  Led by Dr. Heather Leitch, in conjunction with the BC Cancer Agency.

An open-label, study of INCB039110 administered orally to subjects with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV MF) or post essential thrombocythemia myelofibrosis (PET MF) patients.  Led by DR. Lynda Foltz.  One of several new agents being tested for effectiveness in treating myeloproliferative neoplasms (MPN).

A Phase 2, Prospective Study Of  PRM-151 In Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential Thrombocythemia MF (post-ET MF). Dr. Lynda Foltz.

A Phase 3, Randomized, Double-blind Active-controlled Study Evaluating Momelotinib vs. Ruxolitinib in Subjects with Primary Myelofibrosis (PMF) or Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis (Post-PV/ET MF).  Dr. Lynda Foltz.

A Phase 2, Open-label, Randomized Study to Evaluate the Safety and Efficacy of Momelotinib in Subjects with Polycythemia Vera or Essential Thrombocythemia.  Dr. Lynda Foltz.

A Prospective, open-label, multicentre phase 3b study to assess the efficacy and safety of personalized prophylaxis with Human-cl rhFVIII in previously treated adult patients with severe haemophilia A.  Dr. Shannon Jackson.

Coming soon – A randomized trial of a new agent taken with hydroxyurea compared to hydroxyurea alone to decrease the number of acute sickling events in sickle cell anemia.  Dr. Hatoon Ezzat.

Coming soon – A study of ruxolitinib started at a lower dose for patients with myelofibrosis and significant anemia, to optimize hemoglobin levels.  (Impact of ruxolitinib treatment on the hemoglobin dynamics and the negative prognosis of anemia in patients with myelofibrosis. Al-Ali HK, Stalbovskaya V, Gopalakrishna P, Perez-Ronco J, Foltz L. Leuk Lymphoma. 2016 Oct;57(10):2464-7). Dr. Lynda Foltz.

Coming soon – A study of venetoclax plus low dose cytarabine in patients with acute myeloid leukemia not suitable for conventional chemotherapy, such as patients over the age of 65.

OTHER STUDIES

MDS

Parameters influenced by iron overload in an MDS preclinical model.  Bench research recently done by Dr. Heather Leitch in Dr. John Porter’s laboratory at University College Hospital, London, UK.

Current analyses in iron overload include looking at subtypes of MDS to determine whether there are subgroups that derive more or less clinical benefit from reduction of iron overload.  This follows up on the demonstration that RARS may derive less benefit from iron chelation therapy than do other lower risk MDS subtypes.  Dr. Heather Leitch.

We are also looking at whether patients with World Health Organization defined acute myeloid leukemia (AML) who are ineligible for (intensive) AML chemotherapy (usually due to age) but who are receiving and responding to the disease modifying agent Azacitidine, benefit from measures to reduce transfusional iron overload, such as iron chelation therapy or phlebotomy for those achieving transfusion independence.  Outcome measures will include remission duration and overall survival.  Dr. Heather Leitch.

We recently looked at whether iron stores (ferritin levels) could be reduced in MDS by medications that improve hemoglobin levels and delay or reduce transfusion requirements; erythropoiesis stimulating agents in lower risk MDS and Azacitidine in higher risk MDS.  We showed that, although ferritin levels in patients responding to these agents increased less than in non-responders, they still continued to increase (Tsang E, Leitch HA.  Can iron overload in patients with lower-risk myelodysplastic syndromes be reduced using erythropoiesis-stimulating agents?  Ann Hematol. 2016 Jan;95(1):73-8.; Tsang E, Leitch HA.  Pre- and post-treatment serum ferritin levels in patients with higher risk myelodysplastic syndromes receiving azacitidine.  Leuk Lymphoma. 2016 Nov;57(11).

We recently completed an analysis of patients with MDS who present with autoimmune phenomena as a paraneoplastic manifestation of MDS.  This is a recently recognized phenomenon, and can occur in a sizeable minority of patients.  Recommendations for monitoring and management were made (Williamson BT, Foltz L, Leitch HA. Autoimmune Syndromes Presenting as a Paraneoplastic Manifestation of Myelodysplastic Syndromes: Clinical Features, Course, Treatment and Outcome.  Hematol Rep. 2016 May 10;8(2):648.).

We also reported on well-controlled HIV infection presenting with higher risk MDS, and reviewed the literature on this topic.  This presentation may indicate that patients with HIV infection are now living long enough to develop the usual age-related complications, such as MDS (Williamson BT, Leitch HA.  Higher Risk Myelodysplastic Syndromes in Patients with Well-Controlled HIV Infection: Clinical Features, Treatment, and Outcome.  Case Rep Hematol. 2016:8502641).

ACUTE LEUKEMIA

Acute leukemia in patients sixty years of age and older: a twenty year single institution review. Leger CS, Leitch HA, Galbraith PF, Li CH, Vickars LM. Am J Clin Oncol. 2009 Apr;32(2):137-41.  This analysis showed that patients over age 60 with acute leukemia have very suboptimal outcomes that have not improved over the last 20 years.  New treatment approached are needed.

CHRONIC LYMPHOCYTIC LEUKEMIA

Autoimmune Cytopenia in Chronic Lymphocytic Leukemia: Effect on Outcome and Survival, a Population Based Analysis in British Columbia, Canada. Alaa A Alzaki, Alina S Gerrie, Tanya L. Gillan, Steven Huang, Miriam Ahmed, Cynthia L. Toze, Heather A Leitch, Khaled M Ramadan Blood  2014  124:1945.

Clinical Outcomes for Chronic Lymphocytic Leukemia (CLL) Patients with 11q Deletion in British Columbia (BC), Canada: Results of a Population-Based Cohort. Jennifer Goy, Tanya L. Gillan, Huang J.T. Steven, Helene Bruyere, Monica Anne Hrynchak, Aly Karsan, Khaled Ramadan, Adam C. Smith, Cynthia L. Toze, Alina S. Gerrie. Blood  2014  124:2648;

Comparison of Outcomes in Chronic Lymphocytic Leukemia (CLL) with the Addition of Rituximab to Initial Treatment: A Comparative Effectiveness Analysis in the Province of British Columbia (BC), Canada  Lauren J. Lee, Alina S. Gerrie, Helene Bruyere, Tanya L. Gillan, Stephen J.T. Huang, Cynthia L. Toze, Khaled M. Ramadan Blood  2014  124:3344.

HEMOGLOBINOPATHIES

Association Between Increased Liver Iron Concentration and Vitamin D Deficiency in Patients with Transfusion Dependent Hemoglobinopathies in British Columbia  Hatoon Ezzat, John K. Wu, Heather McCartney, Heather A Leitch Blood  2012  120:3203.  Patients with iron overload in the liver may need supplementation of vitamin D to preserve bone health.  Alternatively, those with low vitamin D levels may need more intensive iron chelation therapy so that liver iron does not interfere with vitamin D metabolism.

Utility of Transient Elastography (Fibroscan) in Estimating Hepatic Iron Concentration in Comparison to MRI in Patients with Transfusion Dependent Hemoglobinopathies  Hatoon Ezzat Blood  2014  124:4888.  An easier and less expensive way to measure iron overload in the liver than magnetic resonance imaging (MRI).

Successful Tolerance of Deferasirox Following Desensitization for Significant Skin Rash. Hatoon Ezzat, R. Robert Schellenberg, Heather A Leitch, Linda M Vickars. Blood  2011  118:5280.  Deferasirox is an iron chelation agent.  In a minority of patients, it cannot be tolerated because of severe skin rash.  This study describes a protocol for desensitizing patients to deferasirox so that skin rash no longer occurs.

BLEEDING DISORDERS

Haematuria is not a risk factor of hypertension or renal impairment in patients with haemophilia. Sun HL, Yang M, Sait AS, von Drygalski A, Jackson S. Haemophilia. 2016 Jul;22(4):549-55.

Joining the patient on the path to customized prophylaxis: one hemophilia team explores the tools of engagement. Gue D, Squire S, McIntosh K, Bartholomew C, Summers N, Sun H, Yang M, Jackson S. J Multidiscip Healthc. 2015 Dec 7;8:527-34.

Pain management strategies in adults with haemophilia: a retrospective study. Wang X, Yang M, Jackson S. Haemophilia. 2015 Nov;21(6):e487-9.

HIV

At St. Paul’s Hospital, there is a sizable population of patients with HIV infection, and we are fortunate to have the expertise provided by the Centre for Excellence in HIV/AIDS (CFE) at this site.  Patients with HIV infection present with disorders of the blood, both malignant and non-malignant, regularly, and this is an area of interest in terms of optimizing clinical management.  Several clinical studies have been conducted in the past and present and are planned for the future.  These include:

A review of patients with diffuse large B cell lymphoma, an aggressive non-Hodgkin lymphoma, showed that patients receiving highly active antiretroviral therapy (HAART) could receive the antibody rituximab in conjunction with chemotherapy safely and effectively.  This resulted in BC Cancer Agency approval for the use of this very effective agent, which had been previously withdrawn based on the results of trials conducted elsewhere, for our patients (Improved survival in HIV-associated diffuse large B-cell lymphoma with the addition of rituximab to chemotherapy in patients receiving highly active antiretroviral therapy. Ezzat H, Filipenko D, Vickars L, Galbraith P, Li C, Murphy K, Montaner JS, Harris M, Hogg RS, Vercauteren S, Leger CS, Zypchen L, Leitch HA. HIV Clin Trials. 2007 May-Jun;8(3):132-44.

A review of patients with HIV infection and Burkitt lymphoma, a very aggressive non-Hodgkin lymphoma, conducted in conjunction with colleagues at St. Michael’s and Sunnybrook Hospitals in Toronto and Vancouver General Hospital, showed that patients receiving HAART could receive the aggressive Magrath regimen (CODOX-M/IVAC-R) safely and effectively, and that outcomes were optimized HIV-Associated Burkitt Lymphoma: Good Efficacy and Tolerance of Intensive Chemotherapy Including CODOX-M/IVAC with or without Rituximab in the HAART Era. (Rodrigo JA, Hicks LK, Cheung MC, Song KW, Ezzat H, Leger CS, Boro J, Montaner JS, Harris M, Leitch HA. Adv Hematol. 2012:735392. .

A review of patients with HIV infection and Hodgkin lymphoma conducted in conjunction with St. Michael’s and Sunnybrook Hospitals, showed that patients receiving the protease inhibitors ritonavir and lopinavir had an increased incidence of severe neurotoxicity, presumably from a drug interaction with vinblastine, one of the chemotherapeutic agents used in the Hodgkin-specific treatment regimen ABVD.  In future we would like to measure levels of antiretroviral and chemotherapeutic agents in patients receiving both as an aid in developing a rational treatment strategy for these patients (Incidence, predictors and significance of severe toxicity in patients with human immunodeficiency virus-associated Hodgkin lymphoma. Ezzat HM, Cheung MC, Hicks LK, Boro J, Montaner JS, Lima VD, Harris M, Leitch HA. Leuk Lymphoma. 2012 Dec;53(12):2390-6).

A review of patients with multicentric Castleman disease, a non-malignant but nonetheless highly fatal lymphoproliferation, is in the process of working out the optimal treatment approach based on patients’ clinical and pathological characteristics (Practical Management of Castleman’s Disease.  Alzahrani MF, Radwi M, Leitch HA. Acta Haematol. 2016;136(1):16-22.  Human immunodeficiency virus-associated multicentric Castleman disease refractory to antiretroviral therapy: clinical features, treatment and outcome. Alzahrani M, Hull MC, Sherlock C, Griswold D, Leger CS, Leitch HA. Leuk Lymphoma. 2015 May;56(5):1246-51.)

A review of patients with HIV-related immune thrombocytopenic purpura (ITP) identified a high relapse rate compared to HIV-negative patients with ITP, and a need for better therapies.  This study has generated a lot of interest on a national and international scale, and we would like to develop a protocol for a clinical trial of the new thrombopoesis stimulating agents in these patients (Clinical Features, Treatment, and Outcome of HIV-Associated Immune Thrombocytopenia in the HAART Era. Ambler KL, Vickars LM, Leger CS, Foltz LM, Montaner JS, Harris M, Dias Lima V, Leitch HA. Adv Hematol. 2012;2012:910954. doi: 10.1155/2012/910954.

OTHER

We collaborate with the Center for Blood Research at UBC (http://www.cbr.ubc.ca)! (Design of long circulating nontoxic dendritic polymers for the removal of iron in vivo. Imran ul-haq M, Hamilton JL, Lai BF, Shenoi RA, Horte S, Constantinescu I, Leitch HA, Kizhakkedathu JN. ACS Nano. 2013 Dec 23;7(12):10704-16).