Publications by authors named "Harold Atkins"

88 Publications

Autologous Hematopoietic Stem Cell Transplantation for Liver Transplant Recipients With Recurrent Primary Sclerosing Cholangitis: A Pilot Study.

Transplantation 2021 May 25. Epub 2021 May 25.

Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada. Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, ON, Canada. Department of Pathology, University of Pittsburgh, Pittsburgh, PA. Department of Medical Imaging, University Health Network, Toronto, ON, Canada. Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.

Background: Primary sclerosing cholangitis (PSC) is an indication for liver transplantation, but recurrence after liver transplantation is associated with poor outcomes often requiring repeat transplantation. We investigated whether autologous hematopoietic stem cell transplantation (aHSCT) could be used to stop progression of recurrent PSC and promote operational tolerance.

Methods: Twelve patients with recurrent PSC were fully evaluated and 5 were selected for aHSCT. Autologous hematopoietic stem cells were collected, purified by CD34 immunomagnetic selection and cryopreserved. Immunoablation using busulfan, cyclophosphamide and rabbit anti-thymocyte globulin was followed by aHSCT. The primary endpoint of the study was the establishment of operational tolerance defined as lack of biochemical, histologic and clinical evidence of rejection while off immunosuppression at 2 years post-aHSCT.

Results: Two of the 5 patients achieved operational tolerance with no clinical or histological evidence of PSC progression or allo-rejection. A third patient developed sinusoidal obstruction syndrome following aHSCT requiring repeat liver transplantation but has no evidence of PSC recurrence while on sirolimus monotherapy now more than 3 years after aHSCT. A fourth patient was weaned off immunosuppression but died 212 days after aHSCT from pericardial constriction. A fifth patient died from multiorgan failure. Immunosuppression-free allograft acceptance was associated with deletion of T cell clones, loss of autoantibodies and increases in regulatory T cells, transitional B cells, and programmed cell death protein-1 expressing CD8+ T cells in the 2 long-term survivors.

Conclusions: Although operational tolerance occurred following aHSCT, the high morbidity and mortality observed renders this specific protocol unsuitable for clinical adoption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000003829DOI Listing
May 2021

A real-world single-centre analysis of alemtuzumab and cladribine for multiple sclerosis.

Mult Scler Relat Disord 2021 Jul 11;52:102945. Epub 2021 Apr 11.

University of Ottawa and The Ottawa Hospital Research Institute, Department of Medicine, The Ottawa Hospital General Campus, Multiple Sclerosis Clinic, 501 Smyth Road, Box 601, Ottawa ON K1H 8L6, Canada. Electronic address:

Background: Highly active MS may warrant higher efficacy treatments for disease control. However, these often confer more risk and have not been compared in head-to-head clinical trials, making relative efficacy and safety difficult to interpret. Alemtuzumab and cladribine are two high-efficacy treatments given as discrete courses separated by one year, followed by a durable response that potentially does not require ongoing treatment. Before the approval of oral cladribine, our centre had been treating patients with a bioequivalent intravenous (IV) regimen since 2010. The objective of this study is to report the safety and efficacy data of alemtuzumab and cladribine in a real-world, single centre setting.

Methods: We retrospectively reviewed all patients treated with alemtuzumab or cladribine at the Ottawa Hospital MS Clinic with 2 or more years of follow-up. Information on baseline demographic variables, previous treatment, and prior disease activity was collected. Outcomes investigated were "no evidence of disease activity" (NEDA) and its constituents: new clinical relapse, new MRI activity, and Expanded Disability Status Scale (EDSS) progression; as well as any adverse events or treatment discontinuation. We performed univariate and multiple logistic regression to determine differences in 2-year NEDA and time-to-event analyses with Cox regression models to determine factors associated with each outcome through the study period.

Results: Forty-six patients were treated with alemtuzumab and 65 with cladribine of whom 51 (78%) received the intravenous regimen, followed for a total of 420.1 person-years. The cladribine group was older (p=.0002), with higher baseline EDSS (p=.0015), and more likely secondary progressive (p<.0001). Alemtuzumab had a higher rate of 2-year NEDA than cladribine (OR 4.78, 95%CI: 1.57-14.50, p=.006), but beyond 2 years the difference was not statistically significant (HR 0.50, 95%CI: 0.25-1. 30, p=.061). More prior treatments were associated with lower likelihood of retaining NEDA (HR 1.26, 95%CI: 1.03-1.54, p=.027). Alemtuzumab had more infusion reactions (80% vs. 17%, p<.0001), shingles (22% vs. 2%, p=.005), and secondary autoimmunity (52% vs. 3%, p<.0001) than cladribine, but there was no difference in grade 3 or higher adverse events (21.7% vs. 18.5%, p=1.0).

Conclusion: In our cohort alemtuzumab and cladribine achieved similar rates of NEDA in long-term follow-up, with overall less adverse events with cladribine. Patient registries would allow more robust comparisons, detection of adverse events, and assessment of a durable response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2021.102945DOI Listing
July 2021

Hematologists' barriers and enablers to screening and recruiting patients to a chimeric antigen receptor (CAR) T cell therapy trial: a theory-informed interview study.

Trials 2021 Mar 25;22(1):230. Epub 2021 Mar 25.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada.

Background: Novel therapies often fail to reach the bedside due to low trial recruitment rates. Prior to conducting one of the first chimeric antigen receptor (CAR) T cell therapy trials in Canada, we used the Theoretical Domains Framework, a novel tool for identifying barriers and enablers to behavior change, to identify physician-related barriers and enablers to screening and recruiting patients for an early phase immunotherapy trial.

Methods: We conducted interviews with hematologists across Canada and used a directed content analysis to identify relevant domains reflecting the key factors that may affect screening and recruitment.

Results: In total, we interviewed 15 hematologists. Physicians expressed "cautious hope"; while expressing safety, feasibility, and screening criteria concerns, 14 out of 15 hematologists intended to screen for the trial (domains: knowledge, goals, beliefs about consequences, intentions). Physicians underscored the "challenging contexts," identifying resources, workload, forgetting, and patient wait times to receive CAR T cells as key practical barriers to screening (domains: environmental context and resources, memory, attention and decision-making, behavioral regulation). They also highlighted "variability in roles and procedures" that may lead to missed trial candidates (domain: social and professional role). Left unaddressed, these barriers may undermine trial recruitment.

Conclusions: This study is among the first to use the Theoretical Domains Framework from the physician perspective to identify recruitment challenges to early phase trials and demonstrates the value of this approach for identifying barriers to screening and recruitment that may not otherwise have been elicited. This approach can optimize trial procedures and may serve to inform future promising early phase cancer therapy trials.

Trial Registration: ClinicalTrials.gov Identifier: NCT03765177 . Registered on December 5, 2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-021-05121-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995587PMC
March 2021

Navigating choice in the face of uncertainty: using a theory informed qualitative approach to identifying potential patient barriers and enablers to participating in an early phase chimeric antigen receptor T (CAR-T) cell therapy trial.

BMJ Open 2021 03 19;11(3):e043929. Epub 2021 Mar 19.

Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Objectives: Bench to bedside translation of groundbreaking treatments like chimeric antigen receptor T (CAR-T) cell therapy depends on patient participation in early phase trials. Unfortunately, many novel therapies fail to be adequately evaluated due to low recruitment rates, which slows patient access to emerging treatments. Using the Theoretical Domains Framework (TDF), we sought to identify potential patient barriers and enablers to participating in an early phase CAR-T cell therapy trial.

Design: We used qualitative semistructured interviews to identify potential barriers and enablers to patients' hypothetical participation in an early phase CAR-T cell therapy trial. We used the TDF and directed content analysis to identify relevant domains based on frequency, relevance and the presence of conflicting beliefs.

Participants: Canadian adult patients diagnosed with haematological malignancies.

Results: In total, we interviewed 13 participants (8 women, 5 men). Participants ranged in age from 18 to 73 (median=56) and had been living with haematological cancer from a few months to several years. We found participants were unfamiliar with CAR-T cell therapy but wished to know more about treatment safety, efficacy and trial logistics (domains: knowledge, beliefs about consequences). They were motivated by altruistic considerations, though many prioritised personal health benefits despite recognising the goals (ie, establishing safety) of early phase clinical trials (domains: goals, intentions). Every participant valued receiving medical advice from their haematologists and oncologists, though some preferred impartial medical experts to inform their decision making (domain: social influences). Finally, participants indicated that improving access to financial and social supports would improve their trial participation experience (domain: environmental context and resources).

Conclusion: Using the TDF allowed us to identify factors that might undermine participation to a CAR-T cell therapy trial and to optimise recruitment processes by considering patient perspectives to taking part in early phase trials. NCT03765177; Pre-results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-043929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986876PMC
March 2021

Autologous Hematopoietic Stem Cell Transplantation for Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Can J Neurol Sci 2021 Feb 26:1-7. Epub 2021 Feb 26.

Division of Neurology, The Ottawa Hospital, University of Ottawa, Ottawa, Canada.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) refractory to conventional therapy can lead to marked disability and represents a therapeutic challenge.

Objective: To report five cases of treatment-refractory disabling CIDP treated with autologous hematopoietic stem cell transplantation (AHSCT).

Methods: This was a retrospective cohort study from a tertiary care referral center for both neuromuscular disease and AHSCT. Patients with CIDP treated with AHSCT between 2008 and 2020 were included. All patients had major persistent and disabling neuropathic deficits despite combinations of intensive immunosuppressive therapy. The primary outcome measures were: Medical Research Council sum score, Overall Neuropathy Limitations Scale and requirement for ongoing CIDP immunotherapy after transplantation. We also analyzed safety outcomes by documenting all severe AHSCT-related complications.

Results: Five patients with refractory CIDP underwent AHSCT. Three were classified as manifesting a typical syndrome, two were classified as the multifocal Lewis Sumner variant. The mean age at time of CIDP diagnosis was 33.4 years (range 24-46 years), with a median delay of 46 months (range 21-135 months) between diagnosis and AHSCT. The median follow-up period was 41 months. All five patients were able to wean off CIDP-related immunotherapy. Marked improvements in Medical Research Council scale and overall Neuropathy Limitations Scale were noted in 4/5 patients. One patient with longstanding neurogenic atrophy showed no improvement in disability scales. There were no treatment-related deaths or critical illnesses.

Conclusions: AHSCT can achieve marked sustained clinical improvement of refractory CIDP and may allow for weaning off long-term complex immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2021.30DOI Listing
February 2021

Personalized oncology and BRAF melanoma: model development, drug discovery, and clinical correlation.

J Cancer Res Clin Oncol 2021 May 8;147(5):1365-1378. Epub 2021 Feb 8.

Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, K1H 8L6, Canada.

Purpose: Mutations in BRAF are the most prominent activating mutations in melanoma and are increasingly recognized in other cancers. There is currently no accepted treatment regimen for patients with mutant BRAF melanoma, and the study of melanoma driven by BRAF mutations at the 601 locus is lacking due to a paucity of cellular model systems. Therefore, we sought to better understand the treatment and clinical approach to patients with mutant BRAF melanoma and subsequently develop a novel personalized oncology platform for rare or treatment-refractory cancers.

Methods: We developed and characterized the first patient-derived, naturally occurring BRAF melanoma model, described herein as OHRI-MEL-13, and assessed efficacy using the Prestwick Chemical Library and select targeted therapeutics.

Results: OHRI-MEL-13 exhibits loss of heterozygosity of BRAF, closely mimics the original tumor's gene expression profile, is tumorigenic in immune-deficient murine models, and is available for public accession through American Type Culture Collection. We present in silico modeling data, which illustrates the therapeutic failure of BRAF-targeted therapies in BRAF mutants. Our platform elucidated a unique role for MEK inhibition with cobimetinib, which resulted in short-term clinical success by reducing the metastatic burden.

Conclusion: Our model of BRAF-activated melanoma was developed, thoroughly characterized, and made available for public accession. This model served to demonstrate the feasibility of a novel personalized oncology platform that could be optimized at an institutional level for rare variant or treatment-refractory cancers. We also demonstrate the clinical utility of monotherapy MEK inhibition in a case of BRAF melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-021-03545-2DOI Listing
May 2021

Efficacy and safety of CD22 chimeric antigen receptor (CAR) T cell therapy in patients with B cell malignancies: a protocol for a systematic review and meta-analysis.

Syst Rev 2021 01 21;10(1):35. Epub 2021 Jan 21.

Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

Background: Chimeric antigen receptor (CAR) T cell therapy has had great success in treating patients with relapsed or refractory B cell malignancies, with CD19-targeting therapies now approved in many countries. However, a subset of patients fails to respond or relapse after CD19 CAR T cell therapy, in part due to antigen loss, which has prompted the search for alternative antigen targets. CD22 is another antigen found on the surface of B cells. CARs targeting CD22 alone or in combination with other antigens have been investigated in several pre-clinical and clinical trials. Given the heterogeneity and small size of CAR T cell therapy clinical trials, systematic reviews are needed to evaluate their efficacy and safety. Here, we propose a systematic review of CAR T cell therapies targeting CD22, alone or in combination with other antigen targets, in B cell malignancies.

Methods: We will perform a systematic search of EMBASE, MEDLINE, Web of Science, Cochrane Register of Controlled Trials, clinicaltrials.gov, and the International Clinical Trials Registry Platform. Ongoing and completed clinical trials will be identified and cataloged. Interventional studies investigating CD22 CAR T cells, including various multi-antigen targeting approaches, in patients with relapsed or refractory B cell malignancies will be eligible for inclusion. Only full-text articles, conference abstracts, letters, and case reports will be considered. Our primary outcome will be a complete response, defined as absence of detectable cancer. Secondary outcomes will include adverse events, overall response, minimal residual disease, and relapse, among others. Quality assessment will be performed using a modified Institute of Health Economics tool designed for interventional single-arm studies. We will report a narrative synthesis of clinical studies, presented in tabular format. If appropriate, a meta-analysis will be performed using a random effects model to synthesize results.

Discussion: The results of the proposed review will help inform clinicians, patients, and other stakeholders of the risks and benefits of CD22 CAR T cell therapies. It will identify gaps or inconsistencies in outcome reporting and help to guide future clinical trials investigating CAR T cells.

Systematic Review Registration: PROSPERO registration number: CRD42020193027.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13643-021-01588-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819297PMC
January 2021

Partnering with patients to get better outcomes with chimeric antigen receptor T-cell therapy: towards engagement of patients in early phase trials.

Res Involv Engagem 2020 14;6:61. Epub 2020 Oct 14.

Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada.

Aim: Though patient engagement in clinical research is growing, recent reports suggest few clinical trials report on such activities. To address this gap, we describe our approach to patient engagement in the development of a clinical trial protocol to assess a new immunotherapy for blood cancer (chimeric antigen receptor T-cell therapy, CAR-T cell therapy).

Methods: Our team developed a clinical trial protocol by working with patient partners from inception. Two patient partners with lived blood cancer experience were identified through referrals from our team's professional network and patient organization contacts. Our patient partners were onboarded to the team and engaged in several studies conducted to develop the clinical trial protocol, including a systematic review of the existing literature on the therapy, patient interviews and a survey to obtain perspectives on barriers and enablers to participating in the trial, an early economic analysis, and a retrospective cohort study.

Results: Engaging patient partners enhanced our research in ways that would not have otherwise occurred. By selecting patient important outcomes for data collection, our partners helped flag that quality of life and health utility measures have not been reported in previous CAR-T cell therapy trials for blood cancer. Our partners also co-developed a non-technical summary of the systematic review that summarized results in an accessible manner. Our patient partners reviewed interview and survey questions, to improve the language and appropriateness; provided recruitment suggestions; and provided a patient perspective on the results, thereby confirming the importance of findings. Input was also obtained on costs for the early economic analysis. Our patient partners identified costs that may be a burden to both patients and caregivers during a trial and helped to confirm that the overall structure of the economic model reflected the patient care pathway. Our patient partners also shared their diagnosis and treatment stories, which helped to provide the research team with insight into this experience.

Conclusions: Contributions by our patient partners were invaluable to each component study, as well as the overall development of the trial protocol. We plan to use this approach in the future in order to meaningfully engage patients in the development of other clinical trials; we also hope that by reporting our methods this will help other research teams to do the same.

Trial Registration: Affiliated with the development of NCT03765177.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40900-020-00230-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557015PMC
October 2020

Cyclophosphamide-Glucocorticoids versus Lenalidomide-Dexamethasone as Treatment for Multiple Myeloma at First Relapse after Autologous Stem Cell Transplantation - A Retrospective Analysis.

Hematol Transfus Cell Ther 2020 Sep 13. Epub 2020 Sep 13.

University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

There have been significant improvements in therapeutic options for relapsed multiple myeloma (MM) over the past two decades, with many novel agents including proteasome inhibitors, immunomodulatory agents, and more recently monoclonal antibodies demonstrating efficacy in this setting. However, there is a paucity of real-world data comparing outcomes seen in patients treated with novel agents as opposed to older agents. We report a historical single center cohort of patients diagnosed with myeloma between the years 1991-2012 in order to explore possible differences in outcomes. A total of 139 patients who underwent stem cell transplantation were included in our study. In our study, 88 patients were treated with cyclophosphamide and steroids alone at relapse whereas 51 patients were treated with Len-Dex. In the multivariate analysis, TTNT was shorter for patients who received Cyclo compared to Len-Dex (HR=1.74; 95% CI, 1.01-2.99; p=0.04); however, we could not detect an overall survival benefit (HR=1.20; 95% CI 0.63-2.29; p=0.57). Adverse event rates were similar in the two groups. In this retrospective single center analysis, Len-Dex was associated with longer TTNT compared with Cyclo at first relapse following autoSCT in MM; however its effect on overall survival in this setting was less clear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.htct.2020.07.007DOI Listing
September 2020

Autologous hematopoietic stem cell transplantation for multiple sclerosis: A current perspective.

Mult Scler 2021 02 4;27(2):167-173. Epub 2020 May 4.

Department of Medicine, Division of Neurology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.

The most effective treatment at halting inflammation in patients with highly active multiple sclerosis (MS) is immune ablation followed by autologous hematopoietic stem cell transplantation (AHSCT). Better patient selection and supportive management, as well as advances in conditioning regimens have resulted in improved safety with AHSCT. However, which comorbidities or prior therapies increase the risks associated with AHSCT still need to be determined. In addition, there is still debate as to which AHSCT conditioning regimen offers the best balance of long-term efficacy and safety. New studies comparing AHSCT with highly effective disease-modifying therapies will help to inform on the ideal placement of AHSCT in the treatment algorithm. Currently, many centers are experienced and use AHSCT to treat select patients with MS, contributing to ongoing registries and clinical trials which will help answer these questions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458520917936DOI Listing
February 2021

Neurotoxicity after hematopoietic stem cell transplant in multiple sclerosis.

Ann Clin Transl Neurol 2020 05 18;7(5):767-775. Epub 2020 Apr 18.

The University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada.

Objective: Accelerated brain volume loss has been noted following immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for multiple sclerosis. As with other MS treatments, this is often interpreted as 'pseudoatrophy', related to reduced inflammation. Treatment-related neurotoxicity may be contributory. We sought objective evidence of post-IAHSCT toxicity by quantifying levels of Neurofilament Light Chain (sNfL) and Glial Fibrillary Acidic Protein (sGFAP) before and after treatment as markers of neuroaxonal and glial cell damage.

Methods: Sera were collected from 22 MS patients pre- and post-IAHSCT at 3, 6, 9, and 12 months along with 28 noninflammatory controls. sNfL and sGFAP quantification was performed using the SiMoA single-molecule assay.

Results: Pre-IAHSCT levels of sNfL and sGFAP were elevated in MS patients compared with controls (geometric mean sNfL 21.8 vs. 6.4 pg/mL, sGFAP 107.4 vs. 50.7 pg/mL, P = 0.0001 for both). Three months after IAHSCT, levels of sNfL and sGFAP increased from baseline by 32.1% and 74.8%, respectively (P = 0.0029 and 0.0004). sNfL increases correlated with total busulfan dose (P = 0.034), EDSS score worsening at 6 months (P = 0.041), and MRI grey matter volume loss at 6 months (P = 0.0023). Subsequent NfL levels reduced to less than baseline (12-month geometric mean 11.3 pg/mL P = 0.0001) but were still higher than controls (P = 0.0001). sGFAP levels reduced more slowly but at 12 months were approaching baseline levels (130.7 pg/mL).

Interpretation: There is direct evidence of transient CNS toxicity immediately after IAHSCT which may be chemotherapy mediated and contributes to transient increases in MRI atrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261754PMC
May 2020

Does Lymphocyte Count Impact Dosing of Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplantation?

Biol Blood Marrow Transplant 2020 07 9;26(7):1298-1302. Epub 2020 Mar 9.

Division of Hematology, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada. Electronic address:

Anti-thymocyte globulin (ATG) is used to reduce the incidence and severity of graft-versus-host disease (GVHD) with hematopoietic cell transplantation, yet optimum dosing has yet to be determined. We have previously demonstrated that 2.5 mg/kg ATG in conditioning can reduce the incidence of GVHD in unrelated donor transplants. Recent literature has suggested that ATG dosing based on absolute lymphocyte count (ALC) could lead to more optimum exposure of the drug. We sought to determine if ALC at the time of transplant could impact clinical outcomes. We conducted a retrospective single-center study analyzing all consecutive patients at The Ottawa Hospital who received a matched unrelated donor stem cell transplant with ATG between 2009 and 2014. Patients received rabbit ATG (thymoglobulin) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1. Univariate and multivariate analyses were used to determine if any patient- or transplant-related factors, including weight, ALC, and total ATG dose given, impacted GVHD, relapse, or mortality. In total, 111 patients met inclusion, with a median age of 50 years (range, 19 to 70). The most common diagnoses were acute myelogenous leukemia (43%), Myelodysplasia/myeloproliferative neoplasms (13%), and lymphoma (12%). The median weight at time of conditioning was 80.3 kg (range, 45 to 216). The median ALC on the first day of ATG administration was 0.1 × 10/L (range, 0 to 190). The median total dose of ATG received was 201 mg (range, 112 to 540 mg). The incidence of acute and chronic GVHD was 35.1% and 21.6%, respectively. In the multivariate model, the actual dose of ATG given to patients was not associated with GVHD (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.99 to 1.25; P = .07), relapse (HR, 1.13; 95% CI, 0.98 to 1.30; P = .1), or mortality (HR, 1.09; 95% CI, 0.92 to 1.28; P = .32). Similarly, the pretransplant ALC was not associated with GVHD (HR, 1; P = .82), relapse (HR, 1; P = .90), or mortality (HR, 1; P = .39). If patients had received ALC-based dosing according to previously published work (Admiraal et al., Lancet Haematol 2017), the mean total dose of ATG received would have been 1205 mg, more than 5 times the mean dose that was actually given based on weight. With GVHD outcomes being similar to that published by Admiraal et al. and ALC not independently associated with outcomes in our study, further studies are still needed to compare standard weight-based dosing to ALC-based dosing of ATG in matched unrelated donor stem cell transplant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.02.026DOI Listing
July 2020

Does Resetting the Immune System Fix Multiple Sclerosis?

Can J Neurol Sci 2019 Sep 12:1-10. Epub 2019 Sep 12.

Department of Medicine-Neurosciences, Division of Neurology, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa Hospital, Ottawa, Canada.

Multiple sclerosis is the leading non-traumatic cause of disability in young adults, affecting up to 100,000 Canadians. This chronic inflammatory and neurodegenerative disease of the central nervous system leads to irreversible neurologic disability if inadequately controlled. Though many current medications are available that reduce inflammatory damage, most patients continue to show some evidence of disease activity and accrue disability. In this review, we discuss the role of immune ablation followed by autologous hematopoietic stem cell transplantation (AHSCT), a therapeutic option for select patients with a more aggressive disease course. By "resetting" the immune system with a variety of ablative conditioning regimens, followed by immune reconstitution, this therapy has shown a durable response in halting evidence of inflammatory activity in most patients, without the need for continued disease-modifying therapies (DMT). Since the introduction of this therapy, there have been advances in patient selection and supportive care, such that morbidity has significantly declined and treatment-related mortality is minimized. Recent phase-II trials have shown excellent results in efficacy and safety of AHSCT; however, challenges exist which require ongoing study. The future challenges include comparing the variety of AHSCT conditioning regimens with each other as well as with existing highly effective DMT; identifying patients with an aggressive disease course through novel biomarkers who may benefit the most from AHSCT; and surveillance of long-term outcomes of different treatment protocols. In select patients, replacing the immune system with AHSCT holds promise of fundamentally altering the trajectory of their aggressive disease course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2019.294DOI Listing
September 2019

The impact of multiple myeloma induction therapy on hematopoietic stem cell mobilization and collection: 25-year experience.

Hematol Transfus Cell Ther 2019 Oct - Dec;41(4):285-291. Epub 2019 Jun 14.

The Ottawa Hospital, Ottawa, Canada.

While first-line induction therapy for patients with multiple myeloma has changed over the years, autologous hematopoietic stem cell transplantation still plays a significant role, improving both depth of response and progression-free survival of myeloma patients. Our 25-year experience in mobilizing hematopoietic stem and progenitor cells for 472 transplant-eligible myeloma patients was retrospectively reviewed. Patients were stratified according to the remission induction therapy received, and the outcomes were compared among the cohorts that received vincristine, adriamycin and dexamethasone (VAD) (n=232), bortezomib and dexamethasone (BD) (n=86), cyclophosphamide, bortezomib and dexamethasone (CyBorD) (n=82) and other regimens (n=67). Cyclophosphamide plus granulocyte colony-stimulating factor was the predominant mobilization regimen given. A greater number of CD34 cells (9.9×10E6/kg, p=0.026) was collected with less hospital admissions in BD patients (13%, p=0.001), when compared to those receiving VAD (7.5×10E6/kg, 29%), CyBorD (7.6×10E6/kg, 19%), or other regimens (7.9×10E6/kg, 36%). Induction therapy did not influence the overall rate of unscheduled visits or the length of hospitalization because of complications following mobilization. The myeloma response was not significantly deepened following the cyclophosphamide administered for mobilization. This analysis demonstrates the importance of monitoring the impact of initial treatment on downstream procedures such as stem cell mobilization and collection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.htct.2019.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978537PMC
June 2019

The stem cell market and policy options: a call for clarity.

J Law Biosci 2018 Dec 20;5(3):743-758. Epub 2018 Nov 20.

Faculty of Law and School of Public Health & Health Law Institute, University of Alberta, Edmonton, AB T6G 2H5, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jlb/lsy025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534752PMC
December 2018

Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta-Analysis.

Transfus Med Rev 2019 04 14;33(2):98-110. Epub 2019 Feb 14.

Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada; Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Electronic address:

Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize the efficacy and safety of CAR-T cell therapy in patients with relapsed or refractory hematologic or solid malignancies. MEDLINE, Embase, and the Cochrane Register of Controlled Trials (inception - November 21, 2017). Interventional studies investigating CAR-T cell therapy in patients with malignancies were included. Our primary outcome of interest was complete response (defined as the absence of detectable cancer). Two independent reviewers extracted relevant data, assessed risk of bias, and graded the quality of evidence using established methods. A total of 42 hematological malignancy studies and 18 solid tumor studies met were included (913 participants). Of 486 evaluable hematologic patients, 54.4% [95% CI, 42.5%-65.9%] experienced complete response in 27 CD19 CAR-T cell therapy studies. Of 65 evaluable hematologic patients, 24.4% [95% CI, 9.4%-50.3%] experienced complete response in seven non-CD19 CAR-T cell therapy studies. Cytokine release syndrome was experienced by 55.3% [95% CI, 40.3%-69.4%] of patients and neurotoxicity 37.2% [95% CI, 28.6%-46.8%] of patients with hematologic malignancies. Of 86 evaluable solid tumor patients, 4.1% [95% CI, 1.6%-10.6%] experienced complete response in eight CAR-T cell therapy studies. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. There was a strong signal for efficacy of CAR-T cell therapy in patients with CD19+ hematologic malignancies and no overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and other stakeholders of the benefits and risks associated with CAR-T cell therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tmrv.2019.01.005DOI Listing
April 2019

Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2019 05 19;25(5):845-854. Epub 2019 Feb 19.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.02.014DOI Listing
May 2019

Stem Cell Transplantation to Treat Multiple Sclerosis.

Authors:
Harold Atkins

JAMA 2019 01;321(2):153-155

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2018.20777DOI Listing
January 2019

Another brick in the wall: further evidence supporting the role of haematopoietic stem cell transplantation in treating multiple sclerosis.

Authors:
Harold L Atkins

J Neurol Neurosurg Psychiatry 2019 05 10;90(5):496. Epub 2019 Jan 10.

The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON K1H 8L6, Canada

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2018-319715DOI Listing
May 2019

Autologous hematopoietic stem cell transplantation improves fatigue in multiple sclerosis.

Mult Scler 2019 11 25;25(13):1764-1772. Epub 2018 Sep 25.

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

Background: Fatigue is a common problem in multiple sclerosis (MS) affecting as many as 90% of patients. The Fatigue Impact Scale (FIS) is a validated measure of fatigue in MS patients. The cause of fatigue in MS is likely multifactorial, with some evidence that ongoing central nervous system (CNS) inflammation is a contributing factor. Immunoablation and autologous hematopoietic stem cell transplantation (aHSCT) have been shown to halt ongoing CNS inflammation.

Objective: To investigate whether halting all ongoing inflammation with aHSCT impacts FIS scores in patients with severe MS.

Methods: In the Canadian aHSCT study ( ClinicalTrials.gov , NCT01099930), 23 patients underwent aHSCT and had FIS prospectively collected every 6 months for 36 months of follow-up. Change in FIS was analysed by repeated-measures analysis of variance (RMANOVA) with multiple linear regression to determine independent predictors.

Results: The median FIS score decreased 36%, from 36 to 23 ( = 0.001), and four patients had 100% reduction. Improvement in FIS correlated with lower age and Expanded Disability Status Scale at baseline, as well as increased independence as evidenced by a return to gainful employment and even driving.

Conclusion: Patients had significantly less fatigue on average after aHSCT. This may serve to better understand the contribution of ongoing CNS inflammation to fatigue peculiar to MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458518802544DOI Listing
November 2019

Effect of Donor Age and Donor Relatedness on Time to Allogeneic Hematopoietic Cell Transplantation in Acute Leukemia.

Biol Blood Marrow Transplant 2018 12 21;24(12):2466-2470. Epub 2018 Jul 21.

Department of Medicine (Hematology), University of Ottawa, Ottawa, Ontario, Canada; Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, Ontario, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; OneMatch Stem Cell & Marrow Network, Canadian Blood Services, Ottawa, Ontario, Canada. Electronic address:

Relapse after allogeneic hematopoietic cell transplantation (HCT) for acute leukemia can be reduced when pursued early after first complete remission. The impact of donor age and donor relatedness on the time from diagnosis to transplant in patients with acute leukemia was examined to clarify the design of future prospective studies that can address optimal donor choice. Files of 100 consecutive patients undergoing transplantation for leukemia were reviewed. Recipients of related donors (RDs) and unrelated donors (UDs) were not significantly different in terms of recipient gender, age, underlying diagnosis, disease risk index, graft source, or donor HLA match. UDs were significantly younger than RDs (median age, 29 versus 51, P < .001). Multivariate linear regression revealed that when controlling for age of donor and recipient, the time from diagnosis to transplant was 35% longer with UDs compared with RDs (P = .018). No significant correlation was observed between donor and recipient age on length of time to transplant (P = .134 and P = .850, respectively), when controlling for other variables. The steps in UD procurement that contribute most to the longer time to transplant relate to activating the donor workup and scheduling the donor workup before cell collection. Understanding sources of delay in the transplant process will help transplant centers and UD registries reduce the time to transplant for patients with acute leukemia and will provide necessary insight for the design of prospective controlled studies that can address optimal donor choice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2018.07.022DOI Listing
December 2018

Natural Killer Cells Regulate Th17 Cells After Autologous Hematopoietic Stem Cell Transplantation for Relapsing Remitting Multiple Sclerosis.

Front Immunol 2018 7;9:834. Epub 2018 May 7.

Neuroimmunology Unit, McGill University and Montreal Neurological Institute, Montreal, QC, Canada.

In autoimmunity, the balance of different helper T (Th) cell subsets can influence the tissue damage caused by autoreactive T cells. Pro-inflammatory Th1 and Th17 T cells are implicated as mediators of several human autoimmune conditions such as multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (aHSCT) has been tested in phase 2 clinical trials for MS patients with aggressive disease. Abrogation of new clinical relapses and brain lesions can be seen after ablative aHSCT, accompanied by significant reductions in Th17, but not Th1, cell populations and activity. The cause of this selective decrease in Th17 cell responses following ablative aHSCT is not completely understood. We identified an increase in the kinetics of natural killer (NK) cell reconstitution, relative to CD4 T cells, in MS patients post-aHSCT, resulting in an increased NK cell:CD4 T cell ratio that correlated with the degree of decrease in Th17 responses. removal of NK cells from post-aHSCT peripheral blood mononuclear cells resulted in higher Th17 cell responses, indicating that NK cells can regulate Th17 activity. NK cells were also found to be cytotoxic to memory Th17 cells, and this toxicity is mediated through NKG2D-dependent necrosis. Surprisingly, NK cells induced memory T cells to secrete more IL-17A. This was preceded by an early rise in T cell expression of and mRNA, and could be blocked with neutralizing antibodies against CD58, a costimulatory receptor expressed on NK cells. Thus, NK cells provide initial co-stimulation that supports the induction of a Th17 response, followed by NKG2D-dependent cytotoxicity that limits these cells. Together these data suggest that rapid reconstitution of NK cells following aHSCT contribute to the suppression of the re-emergence of Th17 cells. This highlights the importance of NK cells in shaping the reconstituting immune system following aHSCT in MS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.00834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951114PMC
June 2019

Autologous Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Sclerosis.

Cold Spring Harb Perspect Med 2019 03 1;9(3). Epub 2019 Mar 1.

Department of Medicine-Neurosciences, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada.

Multiple sclerosis (MS) is an autoimmune disorder that typically affects young people during their most productive years, causing irreversible damage and accumulation of disability. Treatments over time have had modest effects at completely controlling or suppressing disease activity, but are generally aimed at controlling early dominating inflammation that, over time, accumulates damage and leads to progressive disability. Some unfortunate patients are destined to deteriorate despite even newer and more effective agents because of the inability of these drugs to fully curb the inflammatory component of the disease. These patients require something more that might be capable of halting the disease process. Using high-intensity myeloablative chemotherapeutic agents, it is now possible to completely remove the peripheral immune system and replace it anew from autologous bone marrow-derived hematopoietic stem cells, purged of disease-causing MS cells. This procedure, referred to as hematopoietic stem cell transplantation (HSCT), produces a new immune system that appears tolerant and no longer attacks the central nervous system (CNS).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/cshperspect.a029082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396341PMC
March 2019

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis.

BMJ Open 2017 12 29;7(12):e019321. Epub 2017 Dec 29.

Faculty of Medicine, University of Ottawa, Ottawa, Canada.

Introduction: Patients with relapsed or refractory malignancies have a poor prognosis. Immunotherapy with chimeric antigen receptor T (CAR-T) cells redirects a patient's immune cells against the tumour antigen. CAR-T cell therapy has demonstrated promise in treating patients with several haematological malignancies, including acute B-cell lymphoblastic leukaemia and B-cell lymphomas. CAR-T cell therapy for patients with other solid tumours is also being tested. Safety is an important consideration in CAR-T cell therapy given the potential for serious adverse events, including death. Previous reviews on CAR-T cell therapy have been limited in scope and methodology. Herein, we present a protocol for a systematic review to identify CAR-T cell interventional studies and examine the safety and efficacy of this therapy in patients with haematology malignancies and solid tumours.

Methods And Analysis: We will search MEDLINE, including In-Process and Epub Ahead of Print, EMBASE and the Cochrane Central Register of Controlled Trials from 1946 to 22 February 2017. Studies will be screened by title, abstract and full text independently and in duplicate. Studies that report administering CAR-T cells of any chimeric antigen receptor construct targeting antigens in patients with haematological malignancies and solid tumours will be eligible for inclusion. Outcomes to be extracted will include complete response rate (primary outcome), overall response rate, overall survival, relapse and adverse events. A meta-analysis will be performed to synthesise the prevalence of outcomes reported as proportions with 95% CIs. The potential for bias within included studies will be assessed using a modified Institute of Health Economics tool. Heterogeneity of effect sizes will be determined using the Cochrane statistic.

Ethics And Dissemination: The review findings will be submitted for peer-reviewed journal publication and presented at relevant conferences and scientific meetings to promote knowledge transfer.

Prospero Registration Number: CRD42017075331.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2017-019321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988064PMC
December 2017

Five Questions Answered: A Review of Autologous Hematopoietic Stem Cell Transplantation for the Treatment of Multiple Sclerosis.

Neurotherapeutics 2017 Oct;14(4):888-893

The Ottawa Hospital, 501 Smyth Rd., Mailstop 926, Ottawa, Ontario, K1H 8L6, Canada.

Multiple sclerosis (MS) is thought to be an autoimmune disease targeting the central nervous system leading to demyelination, and axonal and neuronal damage, resulting in progressive disability. More intensive therapies such as immunodepletion with hematopoietic stem-cell rescue are being used at a time prior to patients becoming irreversibly disabled. Over the last 15 years, there has been a shift away from using autologous hematopoietic stem-cell transplants (aHSCT) to treat patients with progressive MS, towards treating those with active inflammation and relapses. There is an increasing body of evidence that aHSCT improves all measured MS outcomes, including burden of disease on MRI, clinical relapses, accumulation of disability, and quality of life of patients with active MS not controlled with standard therapy. Importantly, the progression-free survival curves of these patients plateau after the first few years demonstrating the impact that aHSCT has in changing the natural history of MS, potentially freeing patients from the relentless accumulation of disability. Concurrently there has been a reduction in procedure-related mortality. The results of randomized trials will likely spur further development of this field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-017-0564-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722769PMC
October 2017

Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2017 Dec 15;23(12):2096-2101. Epub 2017 Aug 15.

Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Department of Medicine, Ottawa, Ontario, Canada; The Ottawa Hospital Bone Marrow Transplant Programme, University of Ottawa, Ottawa, Ontario, Canada. Electronic address:

Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (alloHCT). Prophylactic in vivo T cell depletion with antithymocyte globulin (ATG) has been associated with decreased GVHD rates in many alloHCT settings. Despite decades of clinical study, optimal ATG dosing has not been established. Understanding that higher rates of GVHD are observed with matched unrelated donor (MUD) versus matched related donor (MRD) alloHCT, at our institution MUD alloHCT recipients have historically had low-dose Thymoglobulin (total dose, 2.5 mg/kg; Genzyme-Sanofi, Cambridge, MA) added to our standard MRD GVHD prophylaxis regimen. In this retrospective cohort study we assessed post-HCT the effectiveness of our uniquely low-dose ATG strategy by comparing ATG exposed (MUD) and unexposed (MRD) alloHCT recipients for GVHD and other clinical HCT outcomes. This retrospective single-center study included all HCT patients transplanted for any malignant indication at The Ottawa Hospital from 2009 to 2014. MUD patients received rabbit ATG (Thymoglobulin) at a total dose of 2.5 mg/kg given over 2 days (.5 mg/kg on day -2; 2.0 mg/kg on day -1 before stem cell infusion) in addition to standard GVHD prophylaxis. Primary outcomes assessed were incidence of acute and chronic GVHD, defined as new-onset GVHD requiring systemic immunosuppressive therapy at less or more than 100 days, respectively. Secondary outcomes included disease relapse and survival. There were 110 and 77 patients in the ATG exposed (MUD) and unexposed (MRD) cohorts, respectively. At baseline there were no significant differences in median age at transplant, sex, disease indication or risk index, graft source, conditioning regimen, or intensity between cohorts. A higher proportion of 7/8 mismatched donor transplants (13% versus 3%, P = .02) and a higher median CD34 dose (7.9 versus 4.9 × 10 cells; P < .01) was observed in the ATG exposed cohort. No differences were noted in platelet engraftment. ATG exposed patients had significantly shorter time to neutrophil engraftment than the unexposed cohort (16 versus 19 days, respectively; P < .01). ATG exposed patients had significantly lower rates of GVHD than ATG unexposed patients (57% versus 79%; P = .01), with differences predominantly in rates of chronic GVHD (18% versus 44%, P < .01). At median follow-up of 28 (range, 3 to 69) and 25 (range, 2 to 73) months for survivors in ATG exposed and unexposed cohorts, respectively, no significant differences in overall survival (median overall survival not met for either cohort), relapse incidence (26% versus 29%, P = .73), or relapse-free survival (RFS) (not met in ATG exposed and 26 months in ATG unexposed, P = .22) were observed between groups. The ATG exposed cohort had significantly higher GVHD-free RFS (GRFS) with a 2-year GRFS of 23% versus 3% (P = .003). There were no significant differences between cohorts in proportion of patientswith post-HCT infectious episodes or intensive care unit admissions. Here we report significantly lower rates of chronic GVHD and significant improvement in GRFS in an ATG exposed MUD alloHCT cohort compared with an ATG unexposed MRD cohort. These findings were observed without differences in relapse, survival, infectious complications, or intensive care unit admissions. Our findings highlight the association of unconventionally low-dose ATG with improved GVHD outcomes and suggest a need for prospective study of ATG use in lower doses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2017.08.007DOI Listing
December 2017

Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis.

Mult Scler 2018 07 15;24(8):1055-1066. Epub 2017 Jun 15.

McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

Background: Immunoablation and autologous hematopoietic stem cell transplantation (IA/aHSCT) halts relapses, white matter (WM) lesion formation, and pathological whole-brain (WB) atrophy in multiple sclerosis (MS) patients. Whether the latter was due to effects on gray matter (GM) or WM warranted further exploration.

Objective: To model GM and WM volume changes after IA/aHSCT to further understand the effects seen on WB atrophy.

Methods: GM and WM volume changes were calculated from serial baseline and follow-up magnetic resonance imaging (MRI) ranging from 1.5 to 10.5 years in 19 MS patients treated with IA/aHSCT. A mixed-effects model with two predictors (total busulfan dose and baseline T1-weighted WM lesion volume "T1LV") characterized the time-courses after IA/aHSCT.

Results: Accelerated short-term atrophy of 2.1% and 3.2% occurred in GM and WM, respectively, on average. Both busulfan dose and T1LV were significant predictors of WM atrophy, whereas only busulfan was a significant predictor of GM atrophy. Compared to baseline, a significant reduction in GM atrophy, not WM atrophy, was found. The average rates of long-term GM and WM atrophy were -0.18%/year (standard error (SE): 0.083) and -0.07%/year (SE: 0.14), respectively.

Conclusion: Chemotherapy-related toxicity affected both GM and WM. WM was further affected by focal T1-weighted lesion-related pathologies. Long-term rates of GM and WM atrophy were comparable to those of normal-aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458517715811DOI Listing
July 2018
-->