Publications by authors named "Hans Messner"

97 Publications

Targeted recruitment of optimal donors for unrelated hematopoietic cell transplantation: The Stem Cell Club process.

Hematol Oncol Stem Cell Ther 2020 Dec 20;13(4):220-231. Epub 2020 Apr 20.

Canadian Blood Services, Ottawa, ON, Canada; Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada.

Objective/background: Patients in need of hematopoietic stem cell transplantation often cannot find a suitable HLA-matched donor in their families and rely on unrelated donors. Individuals can register with their country's donor registry either online or at a stem cell drive by providing consent and a tissue sample for typing.

Methods: Stem Cell Club is a donor recruitment organization in Canada that recruits Canadians as stem cell donors. This article outlines the Stem Cell Club's protocol for donor recruitment at stem cell drives including five core components: prescreening, informed consent, registration, tissue sample collection, and reconciliation.

Results: At stem cell drives, recruiters approach individuals from the most-needed demographic groups, catch their attention, explain the purpose of the drive, and prescreen them to ensure eligibility. Recruiters then secure informed consent, educating registrants about the stem cell donation process, the risks involved, the right to withdraw, and donor-patient anonymity. Recruiters subsequently ask registrants to register by providing their contact/demographic information, completing a health questionnaire, and signing a consent form. Recruiters also guide registrants to provide a tissue sample (e.g., buccal swab) for typing. Finally, recruiters reconcile completed registration kits and prepare them for shipment to the donor registry. Data are presented demonstrating the effectiveness of stem cell drives employing this protocol on recruitment of the most-needed donor demographics and of quality donors.

Conclusion: This protocol incorporates best practices for unrelated donor recruitment. It is relevant to donor recruitment organizations worldwide seeking to improve their recruitment efforts and standardize registrant experience.
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http://dx.doi.org/10.1016/j.hemonc.2020.04.001DOI Listing
December 2020

Safety of two-hour intermittent intravenous infusions of tacrolimus in the allogeneic hematopoietic stem cell transplantation unit.

J Oncol Pharm Pract 2021 Jan 17;27(1):33-39. Epub 2020 Mar 17.

Messner Allogeneic Transplant Program, University Health Network, Toronto, Canada.

At our institution, tacrolimus is used as a second-line agent for the prevention and treatment of graft-versus-host-disease in the allogeneic hematopoietic stem cell transplantation (HSCT) unit after patients have experienced a serious or intolerable adverse event to cyclosporine. As per our standard practice, tacrolimus is administered via 2-h intermittent IV infusions (IIVs) every 12 h rather than continuous IV infusion. Shorter infusion times are cautioned due to concerns of higher rates of nephrotoxicity, neurotoxicity and infusion-related reactions, although there is a paucity of data to support this claim. Our primary objective was to evaluate the safety of a 2-h IIV of tacrolimus in an adult HSCT population. We retrospectively reviewed the charts of 104 patients who received tacrolimus by IIV (3574 doses; median = 22, range 1-158, IQR = 28) from 2002 to 2016. Primary outcomes collected include rates of nephrotoxicity, neurotoxicity and infusion-related reactions. One (0.9%) grade 2 infusion-related reaction occurred and resolved without discontinuation of tacrolimus. Of 16 incidences (13.6%) of nephrotoxicity, all but 10 (8.5%) cases resolved. Precipitating factors for nephrotoxicity unrelated to tacrolimus were identified in all 10 cases. There were 41 incidences (35%) of neurotoxicity, of which, 8 (6.8%) were considered serious. All neurotoxicity reverted to baseline or resolved completely. We propose that a 2-h IIV of tacrolimus is a safe method of administration in the adult HSCT setting.
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http://dx.doi.org/10.1177/1078155220908948DOI Listing
January 2021

First Ready, First to Go: Ethical Priority-Setting of Allogeneic Stem Cell Transplant at a Major Cancer Centre.

Healthc Policy 2020 02;15(3):102-115

Former Director of the Allogeneic Stem Cell Transplantation Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON.

Medical advancements have now made it possible to provide allogeneic stem cell transplantation (allo-SCTs) to older patients and use stem cells from less well-matched donors. This has resulted in access to a life-saving modality for a greater number of patients with imminent life-threatening illnesses. However, resources have not always kept pace with innovation and expanded volumes. During the summer of 2015 in the province of Ontario, Canada, inadequate resources contributed to a capacity crisis, resulting in extended wait-lists for allo-SCT across the province. This situation presented unique ethical challenges, including the need for ongoing negotiations with health system partners and nimble process management to ensure timely delivery of care. This article reports on the process one organization used to determine how to equitably allocate scarce allo-SCT resources. With the ever-expanding landscape of new and emerging medical technologies, our experience has implications for the ethics of translating other increasingly expensive health technologies to clinical care.
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http://dx.doi.org/10.12927/hcpol.2020.26127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075446PMC
February 2020

Predictors of the trajectory of cognitive functioning in the first 6 months after allogeneic hematopoietic stem cell transplantation.

Bone Marrow Transplant 2020 05 19;55(5):918-928. Epub 2019 Nov 19.

Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, ON, Canada.

Certain subgroups of patients may be particularly vulnerable to cognitive decline after treatment with allogeneic hematopoietic stem cell transplant (HCT). The objective of this study was to identify predictors of cognitive functioning changes within the first 6 months after HCT. Fifty-eight adults treated with allogeneic HCT (53% male, mean 48 years of age) completed neuropsychological tests of learning/memory, psychomotor efficiency/processing speed, and executive functioning/working memory at three time points: pre-HCT and day 100 and 6 months post transplant. On average, there was significant improvement in learning/memory (p = 0.002), psychomotor efficiency/processing speed (p < 0.0001), and executive functioning/working memory (p < 0.0001), at 6 months. Multilevel modeling identified predictors of divergence from this trajectory; Karnofsky performance status <80 was associated with worsening learning/memory over time; peak severity of acute graft-versus-host disease >=Grade 2 was associated with worsening psychomotor efficiency/processing speed; and greater years of education predicted a faster improvement in psychomotor efficiency/processing speed. Other factors were associated with cognitive functioning over time: higher intelligence quotient (IQ) was associated with better cognitive functioning, and older age, being male, and greater pretransplant comorbidities were associated with worse cognitive functioning. Overall, cognitive performance appears to improve over the first 6 months after transplant. However, pretransplant and posttransplant factors may influence this trajectory.
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http://dx.doi.org/10.1038/s41409-019-0746-3DOI Listing
May 2020

Combination of the Centre for International Blood and Marrow Transplant Registry Risk Score and the Global Severity Score Enhances Prognostic Risk Stratification in Patients Receiving Frontline Therapy for Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2019 09 4;25(9):1761-1769. Epub 2019 Jun 4.

Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada. Electronic address:

The Centre for International Blood and Marrow Transplant Registry (CIBMTR) score has been shown to be prognostic for overall survival (OS) and nonrelapse mortality (NRM) but has been shown in several single-center studies to classify a large proportion of patients with chronic graft-versus-host disease (cGVHD) in the lower risk groups (RG1 to RG2), thereby limiting its prognostic utility for those patients. We evaluate the CIBMTR score, the Global Severity Score (GSS), and a novel risk score developed to improve on the limitations of the CIBMTR with respect to clinically relevant outcomes, including failure-free survival (FFS), in patients receiving frontline systemic treatment for cGVHD. We identified 277 patients between 2002 and 2012 at the Princess Margaret Cancer Centre in Toronto, Canada, who developed cGVHD and were treated with at least 1 line of systemic therapy. cGVHD was graded by GSS, and patients were stratified by CIBMTR. We evaluated OS, NRM, relapse, and FFS within GSS grade groups, as well as CIBMTR RGs, and used a novel prognostic risk score. The median FFS duration was 164 days in the severe GSS group versus 238 days in the moderate-grade group and 304 days in mild-grade group (P= .001). The median FFS duration was 501 days in CIBMTR RG1 versus 291 days in RG2 and 166 days in RG3 to RG6 (P = .003). A novel risk score combining the GSS and CIBMTR scores was prognostic of OS, NRM, and FFS and was able to subdivide patients with cGVHD in CIBMTR RG1 to RG2 into distinct prognostic risk categories. The CIBMTR risk score and the GSS are well correlated with FFS, OS, and NRM following frontline systemic treatment for cGVHD. A new risk score model combining the CIBMTR risk score and the GSS could enhance risk stratification in the lower CIBMTR risk groups.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.029DOI Listing
September 2019

Equally Interchangeable? How Sex and Gender Affect Transplantation.

Transplantation 2019 06;103(6):1094-1110

Liver Transplantation & Hepatology Unit, Hospital Universitario La Fe, IIS La Fe, University of Valencia-CIBEReHD, Valencia, Spain.

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.
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http://dx.doi.org/10.1097/TP.0000000000002655DOI Listing
June 2019

Influence of FLT3-ITD and NPM1 status on allogeneic hematopoietic cell transplant outcomes in patients with cytogenetically normal AML.

Eur J Haematol 2019 Apr 13;102(4):368-374. Epub 2019 Feb 13.

Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Objective: In individuals with cytogenetically normal (CN) AML, disease risk is estimated using molecular features such as the status of NPM1 and FLT3-ITD genes. However, data regarding the impact of NPM1 and FLT3-ITD status on hematopoietic stem cell transplant (HCT) outcomes are limited. We examined the effect of NPM1 and FLT3-ITD status on transplant outcomes in 131 CN AML patients transplanted at Princess Margaret Hospital between 2006 and 2017.

Methods: Overall survival (OS) was calculated using Kaplan-Meier analysis and multivariable Cox proportional hazards regression. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated using competing risk regression.

Results: There was no difference in 3-year OS among NPM1 /FLT3-ITD , NPM1 /FLT3-ITD , NPM1 /FLT3-ITD and NPM1 /FLT3-ITD patients: 56% (95% CI, 29%-76%), 61% (95% CI, 46%-73%), 53% (95% CI, 34%-70%) and 52% (95% CI, 17%-78%), respectively. CIR at 3-years was similar among NPM1 /FLT3-ITD , NPM1 /FLT3-ITD and NPM1 /FLT3-ITD patients-14% (95% CI, 6%-26%), 13% (95% CI, 4%-28%) and 19% (95% CI, 4%-41%), respectively-while there were no relapses in the NPM1 /FLT3-ITD group. NRM at 3 years for NPM1 /FLT3-ITD , NPM1 /FLT3-ITD , NPM1 /FLT3-ITD and NPM1 /FLT3-ITD patients was similar at 44% (95% CI, 19%-67%), 38% (95% CI, 25%-50%), 43% (95% CI, 25%-59%) and 44% (95% CI, 14%-71%), respectively.

Conclusion: NPM1 and FLT3-ITD status may provide limited prognostic information about transplant outcomes in CN AML patients.
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http://dx.doi.org/10.1111/ejh.13216DOI Listing
April 2019

Mobilization of Leukemic Cells Using Plerixafor as Part of a Myeloablative Preparative Regimen for Patients with Acute Myelogenous Leukemia Undergoing Allografting: Assessment of Safety and Tolerability.

Biol Blood Marrow Transplant 2019 06 14;25(6):1158-1163. Epub 2019 Jan 14.

Messner Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myelogenous leukemia (AML); however, a major cause of treatment failure is disease relapse. The purpose of this single-center Phase I study was to determine the safety and tolerability of administration of the CXCR4 inhibitor plerixafor (Mozobil; Sanofi Genzyme) along with myeloablative conditioning in patients with AML undergoing allogeneic HCT. The rationale was that plerixafor may mobilize leukemic stem cells, making them more susceptible to the conditioning chemotherapy (registered at ClinicalTrials.gov; identifier NCT01141543). Three patients were enrolled into each of 4 sequential cohorts (12 patients total). Patients in the first cohort received 1 dose of plerixafor (240 μg/kg s.c.) before the first dose of fludarabine and busulfan, and subsequent cohorts received injections before 2, 3, and 4 days of conditioning chemotherapy. The median age at HCT was 49 years (range, 38 to 58 years). All patients engrafted following HCT, with an absolute neutrophil count ≥.5 × 10/L observed at a median of 14 days (range, 11 to 18 days). Adverse events possibly related to plerixafor were transient and not severe. Main adverse events following the injection were nausea and dizziness in 4 patients (33%) and fatigue in 4 patients (33%). Among the 12 patients, 2 patients (17%) relapsed post-HCT and 6 (50%) were alive at the last follow-up. The median follow-up of survivors was 67 months (range, 53 to 82 months). In conclusion, plerixafor administration is safe and well tolerated when included in a myeloablative conditioning regimen for allogeneic HCT for AML. Further study in a larger cohort is warranted for the investigation of the impact of plerixafor on post-allogeneic HCT outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.014DOI Listing
June 2019

Reduced-Intensity Conditioning and Dual T Lymphocyte Suppression with Antithymocyte Globulin and Post-Transplant Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Haploidentical Hematopoietic Stem Cell Transplants for Hematological Malignancies.

Biol Blood Marrow Transplant 2018 11 7;24(11):2259-2264. Epub 2018 Aug 7.

Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada. Electronic address:

Haploidentical hematopoietic stem cell transplantation (haploHSCT) with conditioning regimens using post-transplant cyclophosphamide (PTCy) for peripheral blood stem cell (PBSC) grafts is limited by comparably higher rates of acute and chronic graft-versus-host disease (GVHD). Antithymocyte globulin (ATG) may mitigate this risk. We evaluated haploHSCT after reduced-intensity conditioning (RIC) with ATG, PTCy, and cyclosporine to prevent rejection and GVHD. Fifty adults underwent haploHSCT from August 2016 to February 2018. RIC included fludarabine (30 mg/m/day on days -5 to -2), busulfan (3.2 mg/m/day on days -3 and -2), and total body irradiation (200 cGy) on day -1. Unmanipulated PBSCs were infused on day 0. GVHD prophylaxis included ATG (4.5 mg/kg over days -3 to -1), PTCy (50 mg/kg/day on days +3 and +4), and cyclosporine from day +5. Median age was 56 years (range, 22 to 70 years); 25 (73.5%) patients were in first complete remission (CR1), 5 (14.7%) were in second complete remission (CR2), and 8 (23.5%) had active disease. Median time to neutrophil engraftment was 16 days (range, 8 to 43 days). At day +100, the cumulative incidence of acute GVHD of any grade, and grades III to IV was 38.3% and 5.2%, respectively. Mild chronic GVHD was seen in 15.5%. Cytomegalovirus (CMV) reactivation occurred in 37 (74%) cases and CMV disease occurred in 4 (11.5%) cases. Epstein-Barr virus (EBV) reactivation occurred in 21 (61.8%) patients. The incidence of histologically confirmed post-transplantation lymphoproliferative disorder (PTLD) was 5.8%. Four patients received rituximab. There were no CMV, EBV, or PTLD-related deaths. Six-month and 1-year overall survival (OS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) were 73.9%, 10.2%, and 19.4%, respectively, and 48.1%, 16% and 38.2%, respectively. Infection was the most common cause of death (18%). Unmanipulated haploidentical PBSC transplantation following RIC with ATG, PTCy, and cyclosporine as a GVHD prevention strategy results in low rates of acute and chronic GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110605PMC
November 2018

Fludarabine and busulfan plus low-dose TBI as reduced intensity conditioning in older patients undergoing allogeneic hematopoietic cell transplant for myeloid malignancies.

Ann Hematol 2018 Oct 11;97(10):1975-1985. Epub 2018 Jun 11.

Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Ave, Toronto, ON, M5G 2M9, Canada.

We have been using a combination of fludarabine/busulfan plus low-dose total body irradiation (TBI) as the reduced-intensity conditioning (RIC) regimen for patients age ≥ 60 years undergoing allogeneic hematopoietic cell transplantation (HCT) for myeloid malignancies. We retrospectively analyzed outcomes of 116 older patients (median age 64 years) who underwent HCT from 2006 to 2015 for myeloid malignancies, including acute myeloid leukemia (AML) in first complete remission (CR1). On univariate analysis, overall survival (OS) for the cohort at 3 years was 33% (95% CI 25-42). Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 3 years were 24% (95% CI 16-32) and 43% (95% CI 34-52), respectively. Multivariable analysis for OS demonstrated AML patients to have superior outcome (HR 1.60 for other myeloid, 95% CI 1.01-2.54, p = 0.045), as well as related donors (HR 1.92 for unrelated, 95% CI 1.22-3.03, p = 0.005). For NRM, AML patients had superior outcome (HR 1.76 for other myeloid, 95% CI 1.03-3.01, p = 0.038), as well as patients with related donors (HR 1.81 for unrelated, 95% CI 1.07-3.07, p = 0.028). We then demonstrated that AML patients with related donors (n = 45) had superior 3-year OS of 51% (95% CI 36-65), compared to 21% (95% CI 12-32) for all other patients (p = 0.0003). We conclude that the RIC regimen used is effective for older patients, particularly AML patients in CR1 with matched related donors.
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http://dx.doi.org/10.1007/s00277-018-3391-9DOI Listing
October 2018

Efficacy of Cidofovir in Treatment of BK Virus-Induced Hemorrhagic Cystitis in Allogeneic Hematopoietic Cell Transplant Recipients.

Biol Blood Marrow Transplant 2018 09 18;24(9):1901-1905. Epub 2018 Apr 18.

Division of Hematology, Department of Medicine, London Health Sciences Centre, London, Ontario, Canada.

BK virus-associated hemorrhagic cystitis (BK-HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), with incidences up to 70%. Cidofovir is an antiviral agent with growing evidence as a therapeutic intervention. To assess the safety profile and efficacy of intravenous and intravesical cidofovir in allo-HCT patients with BK-HC, a retrospective study was undertaken of the allo-HCT cohort who received cidofovir for symptomatic BK-HC (hematuria with BK viruria or viremia) from January 2010 until March 2017 in a single transplant center in Ontario, Canada. The primary outcome measure was a reduction in BK-HC severity (graded from 1 to 4); secondary outcomes included overall survival, BK virus titers, and the onset of acute kidney injury. Twelve allo-HCT patients received cidofovir for BK-HC, with pretreatment clinical severity of 3 (50%) or 4 (50%). Cidofovir was administered via intravenous (33%), intravesical (58%), or both modalities (8%). After a median cumulative dose of 10 mg/kg (range, 1 to 37), mean BK-HC grade decreased significantly by 1.8 (3.5 precidofovir, 1.7 postcidofovir, P < .01). Sixty-six percent of patients had at least partial response to cidofovir, with similar response rates between intravenous (66%) and intravesical (62%) administration. Sixty-seven percent of patients died, and 33% of patients experienced renal toxicity, including 2 patients receiving intravesical therapy. In this retrospective series, there was a significant reduction in BK-HC severity after cidofovir administration; most patients achieved at least partial response after cidofovir administration. Even with intravesical instillation, acute kidney injury remains a potential complication of cidofovir. Although cidofovir may be an efficacious therapy for BK-HC, albeit with potential demonstrated toxicities, further prospective trials are needed.
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http://dx.doi.org/10.1016/j.bbmt.2018.04.009DOI Listing
September 2018

Quality of life trajectories during the first year following hematopoietic cell transplantation: an inception cohort study.

Support Care Cancer 2018 Jul 8;26(7):2379-2386. Epub 2018 Feb 8.

Princess Margaret Cancer Centre, Toronto, ON, Canada.

Background: Allogeneic hematopoietic cell transplantation (HCT) affects quality of life (QOL). Patient-reported outcomes examine symptoms, side effects, distress, and physical and social problems, but positive outcomes have been ignored. This inception cohort study followed people over the first year following HCT to document positive and negative outcomes.

Methods: People with hematologic cancers treated by HCT completed complementary self-report instruments at four milestones: (a) pre-transplant (N = 88); (b) engraftment (N = 80); (c) short-term post-discharge (N = 60); and (d) long-term post-discharge (N = 45). We examined symptoms, side effects, illness intrusiveness, depressive symptoms, positive and negative affect, and self-esteem. We compared QOL in HCT with diverse published values.

Results: QOL deteriorated following HCT. Most variables returned to baseline by short-term post-discharge, but self-esteem and illness intrusiveness required more time. Illness intrusiveness at 1 year post-discharge was higher in HCT than other cancer groups; negative affect, too, was higher, but HCT survivors also reported higher positive affect. HCT and other cancer survivors reported similar depressive symptom levels. Compared to healthy people, HCT survivors reported more severe depressive symptoms, but similar positive and negative affect.

Conclusions: QOL changes dramatically following HCT. People report more interference with valued activities and interests after 1 year than survivors of other cancers, but depressive symptoms are not higher. Positive and negative affect are equivalent to healthy community residents. Continued involvement in psychologically meaningful activities may preserve QOL.
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http://dx.doi.org/10.1007/s00520-018-4059-7DOI Listing
July 2018

Reduction of severe acute graft-versus-host disease using a combination of pre transplant anti-thymocyte globulin and post-transplant cyclophosphamide in matched unrelated donor transplantation.

Bone Marrow Transplant 2018 03 21;53(3):361-365. Epub 2017 Dec 21.

Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

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http://dx.doi.org/10.1038/s41409-017-0053-9DOI Listing
March 2018

Therapeutic efficacy of azathioprine in addition to prednisone-based regimens as first-line chronic graft-versus-host disease treatment.

Bone Marrow Transplant 2018 03 15;53(3):334-338. Epub 2017 Dec 15.

Allogeneic Blood And Marrow Transplant Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, 610 University Ave. Toronto, Ontario, Canada, M5G2M9.

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http://dx.doi.org/10.1038/s41409-017-0025-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861088PMC
March 2018

Outcome following second allogeneic hematopoietic cell transplantation: A single-center experience.

Eur J Haematol 2018 Mar 11;100(3):308-314. Epub 2018 Jan 11.

Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.

Objective: Second allogeneic hematopoietic cell transplantation (HCT) may be indicated following relapse or graft failure following first HCT. Our retrospective single-center study sought to investigate parameters that influence post-second allogeneic HCT survival.

Method: We investigated 92 patients who underwent second allogeneic HCT between 1980 and 2016 for relapse or graft failure following first HCT. Median age at second HCT was 41 years (range 16-68), performed for relapse in 59 patients (64%) and for graft failure in 33 patients (36%).

Results: On univariate analysis, 3-year OS of the entire cohort was 35% (95% CI=25-45). Eastern Cooperative Oncology Group (ECOG) score (3-year OS 48% for ECOG 0-1, 18% for ECOG 2-3, P=.0006), second HCT indication (3-year OS 43% for relapse, 20% for graft failure, P=.02), time from first HCT to relapse/graft failure (3-year OS for <12months 21%, for ≥12months 46%, P=.009), and conditioning intensity (3-year OS for MA 42% vs other regimens 23%, P=.08) significantly influenced OS. Multivariable analysis confirmed ECOG score (HR=2.15 for ECOG 2-3, 95% CI=1.32-3.51, P=.002) and second HCT indication (HR=1.67 for graft failure, 95% CI=1.02-2.75, P=.04) to independently influence survival.

Conclusion: Second HCT may offer long-term survival particularly to patients with good performance status who relapse post-first HCT.
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http://dx.doi.org/10.1111/ejh.13015DOI Listing
March 2018

Impact of comorbidities constituting the hematopoietic cell transplant (HCT)-comorbidity index on the outcome of patients undergoing allogeneic HCT for acute myeloid leukemia.

Eur J Haematol 2018 Feb 13;100(2):198-205. Epub 2017 Dec 13.

Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

Objective: To investigate the prognostic impact of the individual component comorbidities of the hematopoietic cell transplant comorbidity index (HCT-CI) in patients with acute myeloid leukemia (AML) that underwent allogeneic hematopoietic cell transplant (HCT).

Method: This single-center study retrospectively investigated the individual comorbidities of the HCT-CI on the outcome of 418 patients that underwent HCT for AML, in CR1 (n = 303, 72%) or CR2 (n = 115, 28%) at our center between 1999 and 2014.

Results: Median age at HCT was 50 years (range 18-71). Univariate analysis of the HCT-CI, grouped as score 0 (n = 109), 1-2 (n = 157) and ≥3 (n = 152), demonstrated significant influence on overall survival (OS) (P = .004) and non-relapse mortality (NRM) (P = .02). For individual comorbidities constituting the HCT-CI, variables with a P-value ≤ .2 on univariate analysis were included in the multivariable analysis. For OS, none of the comorbidities of the HCT-CI demonstrated independent prognostic relevance. However, for NRM, multivariable analysis demonstrated pretransplant diabetes (HR = 2.17, 95% CI = 1.31-3.60, P = .003) and cardiovascular comorbidity (HR = 1.78, 95% CI = 1.15-2.76, P = .01) to be independent predictors of NRM post-transplant.

Conclusion: Among the comorbidities that compose the HCT-CI, diabetes and cardiovascular comorbidity independently predict NRM in patients undergoing allogeneic HCT for AML. This information should be taken into consideration regarding post-transplant monitoring and care.
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http://dx.doi.org/10.1111/ejh.13000DOI Listing
February 2018

Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2018 02 3;24(2):366-372. Epub 2017 Oct 3.

Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Allogenic hematopoietic stem cell transplant (HCT) recipients are at risk of many infections. Nontuberculous mycobacteria (NTM) are increasingly recognized as clinically significant pathogens in this population. We investigated the incidence and risk factors for NTM infection after allogeneic HCT. This retrospective cohort study included all patients with allogeneic HCT at our institution during 2001 to 2013. Patients who developed significant NTM infection (NTM disease) were identified. Multivariable modeling was used to identify risk factors for NTM disease, and a risk score model was constructed to identify high-risk patients. Of 1097 allogeneic HCT patients, 45 (4.1%) had NTM isolated and 30 (2.7%) had NTM disease (28 [93.3%] exclusively pulmonary, 2 [6.7%] pulmonary plus another site). Incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9% to 4.0%). The median time to diagnosis was 343 days (range, 19 to 1967). In Fine-Gray proportional hazards modeling, only global severity of chronic graft-versus-host disease (cGVHD) (HR, 1.99; 95% CI, 1.12 to 3.53; P = .019,) and cytomegalovirus (CMV) viremia (HR, 5.77; 95% CI, 1.71 to 19.45; P = .004) were significantly associated with NTM disease. Using these variables a risk score was calculated: 1 point for CMV viremia or moderate cGVHD and 2 points for severe cGVHD. The score divided patients into low risk (0 to 1 points, n = 820 [77.3%], 3-year NTM risk 1.2%), intermediate risk (2 points, n = 161 [15.4%], 3-year NTM risk 7.1%), and high risk (3 points, n = 56 [5.4%], 3-year NTM risk 14.3%). NTM disease after allogeneic HCT is common. Severe cGVHD and CMV viremia are associated with increased risk, permitting risk stratification.
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http://dx.doi.org/10.1016/j.bbmt.2017.09.015DOI Listing
February 2018

The Stem Cell Club: a model for unrelated stem cell donor recruitment.

Transfusion 2017 12 24;57(12):2928-2936. Epub 2017 Sep 24.

Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Patients with blood, immune, or metabolic diseases may require a stem cell transplant as part of their treatment. However, 70% of patients do not have a suitable human leukocyte antigen match in their family, and need an unrelated donor. Individuals can register as potential donors at stem cell drives, where they provide consent and a tissue sample for human leukocyte antigen typing. The ideal donors are young, male, and from a diversity of ethnic backgrounds. However, in Canada, non-Caucasian males ages 17 to 35 years represent only 8.8% of listed donors.

Study Design And Methods: The Stem Cell Club is a non-profit organization founded in 2011 in Canada that aims to augment recruitment of the most needed donors. The initiative published a recruitment toolkit online (www.stemcellclub.ca). Currently, there are 12 chapters at universities across Canada.

Results: To date, the Stem Cell Club has recruited 6585 potential registrants, representing 1.63% of donors on Canada's donor-database. Of the recruited registrants, 58.3% were male; 60.3% of males self-reported as non-Caucasian, and 78.5% were ages 17 to 25 years. From 2015 to 2016, the initiative recruited 13.7% of all ethnically diverse males ages 17 to 35 years listed in Canada's donor database. Data from this initiative demonstrate sustainability and performance on key indicators of stem cell drive quality.

Conclusion: The Stem Cell Club has developed a capacity to recruit 2600 donors annually, with the majority being males with a high degree of ethnic diversity. The initiative enhances the quality of Canada's unrelated donor-database, improving the chances that patients in need of an unrelated donor will find a match for transplant. The Stem Cell Club is a model relevant to recruitment organizations around the world.
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http://dx.doi.org/10.1111/trf.14327DOI Listing
December 2017

Extramedullary disease at diagnosis of AML does not influence outcome of patients undergoing allogeneic hematopoietic cell transplant in CR1.

Eur J Haematol 2017 Sep 23;99(3):234-239. Epub 2017 Jun 23.

Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Objective: Extramedullary disease (EMD) at diagnosis of acute myeloid leukemia (AML) has been associated with increased risk of relapse and worse outcomes post-chemotherapy. This study sought to investigate the association of EMD with outcomes following allogeneic hematopoietic cell transplantation (allo-HCT).

Methods: This single-center retrospective study investigated the impact of EMD at diagnosis on the outcome of patients transplanted for AML in first complete remission (CR1). The study included 303 consecutive patients with AML transplanted in CR1, median age 51 years (range 18-71).

Results: EMD at diagnosis was documented in 39 patients (13%), either histologically (26 patients) or clinically/radiologically (13 patients). Among the 39 EMD patients, 16 had CNS disease, seven had gingival infiltration, and five had leukemia cutis. On univariate analysis, EMD had no significant impact on survival, with a 3-year OS of 55% (95% CI 38-69) compared to 48% for the non-EMD group (95% CI 42%-55%) (P=.84). Likewise, 3-year CIR was 18% vs 19% (P=.86) and 3-year NRM was 26% vs 33% (P=.83) for EMD vs non-EMD groups, respectively. Multivariate analysis confirmed these results.

Conclusions: We conclude that EMD at diagnosis of AML does not seem to influence outcomes following allo-HCT performed in CR1.
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http://dx.doi.org/10.1111/ejh.12909DOI Listing
September 2017

Distinctive clinical characteristics and favorable outcomes in patients with large granular lymphocytosis after allo-HCT: 12-year follow-up data.

Eur J Haematol 2017 Aug 30;99(2):160-168. Epub 2017 May 30.

Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.

An increase in large granular lymphocytes (LGL) is frequently seen in patients following allogeneic hematopoietic cell transplantation (allo-HCT) and it has been associated with better outcomes in some reports. We assessed 826 consecutive patients at our institution with over 12 years of follow-up for the occurrence of LGL lymphocytosis after allo-HCT. The 3-year cumulative incidence of LGL lymphocytosis was 14.5% with a median duration of over 3.5 years. The development of LGL lymphocytosis was strongly correlated with CMV viremia and GVHD. The clinical course of patients with LGL lymphocytosis after allo-HCT was indolent, with the majority of these patients not displaying any clinical signs or symptoms related to the LGL proliferation. LGL lymphocytosis was associated with better outcomes, including higher overall survival (OS 86.6% vs 44.7% at 3 years), lower non-relapse mortality (NRM 5.5% vs 30.4% at 3 years), and lower risk of relapse (8.9% vs 22.9% at 3 years). A time-dependent multivariable analysis confirmed the favorable impact of LGL lymphocytosis on OS and NRM, but not on the risk of relapse. In multivariable analysis, a longer duration of LGL lymphocytosis was associated with better OS and NRM. Improved immunomodulatory properties of these cells, regulating GVHD and infections, may explain the observed favorable outcomes of patients who developed LGL lymphocytosis following allo-HCT.
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http://dx.doi.org/10.1111/ejh.12899DOI Listing
August 2017

Progressive multifocal leukoencephalopathy due to John Cunningham (JC) virus following allogeneic haematopoietic cell transplantation.

Antivir Ther 2017 ;22(8):721-725

Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Progressive multifocal leukoencephalopathy (PML) is an uncommon infectious complication post allogeneic stem cell transplant. We present a case report of a patient developing this complication with a review of the current literature. It also describes the first use of artesunate in a clinical case of PML with no beneficial effect.
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http://dx.doi.org/10.3851/IMP3162DOI Listing
July 2019

Long-Term Incidence of Secondary Malignancies after Allogeneic Hematopoietic Cell Transplantation: A Single-Center Experience.

Biol Blood Marrow Transplant 2017 Jun 27;23(6):945-951. Epub 2017 Feb 27.

Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

To review the emergence of secondary malignancies (SMs) in recipients of allogeneic hematopoietic cell transplantation (HCT), we documented the occurrence of SMs in 2415 allogeneic HCT recipients, ages 18 to 71, in a single center over 4 decades. SMs were seen in 209 patients, including 58 with nonmetastatic squamous cell (SCC) and basal cell carcinoma (BCC) of the skin. Cumulative incidence of SM was 6.3% at 10 years, 13.5% at 20 years, and 17.6% at 30 years post-HCT. Median age at diagnosis of SMs was 61 years (range, 21 to 85). By multivariable analysis, older age at HCT was the only independent prognostic factor for SM (HR, 1.39 for ages 41 to 55 and HR, 1.92 for age > 55 compared with age ≤ 40; P = .001). The rate of SM (excluding nonmetastatic SCC/BCC of skin) after HCT was 2.07 times higher (P = .01) compared with the general population. Overall survival (OS) after diagnosis of SM (excluding nonmetastatic SCC/BCC of skin) was 58% at 5 years and 50% at 10 years postdiagnosis. Eastern Cooperative Oncology Group (ECOG) score was the only independent predictor of OS on multivariable analysis, with over 2-fold increased risk of death for patients with an ECOG score of 1 and over 6-fold for ECOG scores of 2 to 4, compared with ECOG score 0 (P < .0001). Forty of 209 patients (19%) diagnosed with SMs subsequently developed another new malignancy. OS was 68% and 51% at 5 and 10 years, respectively. The survival of SM patients post-HCT is favorable, thus warranting diligent long-term cancer screening and standard of care treatment. ECOG status of these patients is a predominant prognostic factor.
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http://dx.doi.org/10.1016/j.bbmt.2017.02.015DOI Listing
June 2017

Improved prognostic stratification power of CIBMTR risk score with the addition of absolute lymphocyte and eosinophil counts at the onset of chronic GVHD.

Ann Hematol 2017 May 18;96(5):805-815. Epub 2017 Feb 18.

Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, 610 University Ave, Toronto, ON, M5G2M9, Canada.

The CIBMTR chronic graft-versus-host disease (cGVHD) risk score can be refined and improved for better prognostic stratification. Three hundred and seven consecutive patients diagnosed with cGVHD by the NIH consensus criteria were retrospectively reviewed and had the CIBMTR risk score applied and analyzed. The CIBMTR risk score was successfully validated in our cohort (n = 307). The 3-year overall survival (OS) rates in each risk group (RG) were 82.5 ± 11.3% (RG1), 79.4 ± 3.0% (RG2), 71.8 ± 6.3% (RG3), and 27.3 ± 13.4% (RG4). A significantly lower OS rate and higher non-relapse mortality (NRM) were noted in RG4 compared to the other RGs. However, there were no differences in OS or NRM among RG1 to 3. To improve prognostic stratification power of the CIBMTR risk score, we incorporated the absolute lymphocyte (ALC) and eosinophil count (EC) at time of cGVHD into the CIBMTR risk score. Lower ALC (<1.0 × 10/L, HR 1.94, p = 0.014) and lower EC (<0.5 × 10/L, HR 3.27, p = 0.014) were confirmed as adverse risk factors for OS. Patients were stratified into four revised risk groups (rRG). The 3-year OS rates were 93.3 ± 6.4% (rRG1, score 0-3), 84.9 ± 3.4% (rRG2, score 4-6), 70.9 ± 4.4% (rRG3, score 7-9), and 32.0 ± 1.1% (rRG4, score ≥ 10) (p < 0.001). The 3-year NRM rates were 0.0% (rRG1), 6.7 ± 0.4% (rRG2), 18.4 ± 0.7% (rRG3), and 57.7 ± 5.1% (rRG4) (p < 0.001). The revised CIBMTR risk score was superior to the original CIBMTR risk score for OS (p < 0.001). The revised CIBMTR risk score including ALC and EC at the onset of cGVHD improved the prognostic stratification power of the CIBMTR risk score for long-term outcomes.
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http://dx.doi.org/10.1007/s00277-017-2939-4DOI Listing
May 2017

Myeloablative versus Reduced-Intensity Conditioning in Patients with Myeloid Malignancies: A Propensity Score-Matched Analysis.

Biol Blood Marrow Transplant 2016 12 3;22(12):2270-2275. Epub 2016 Sep 3.

Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Reduced-intensity conditioning (RIC) has been shown to have similar overall survival (OS) but higher relapse rates compared with myeloablative (MAC) regimens in patients with myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Using propensity score matching (PSM) analysis, well-balanced pairs of different variables can be compared effectively. We retrospectively compared allo-HSCT recipients with acute myeloid leukemia or myelodysplasia receiving a RIC regimen (FBT200; fludarabine 30 mg/m/day for 4 days, busulfan 3.2 mg/kg/day for 2 days, and total body irradiation [TBI] 200 cGy) or MAC regimen (FBT400; fludarabine 50 mg/m/day for 4 days, busulfan 3.2 mg/kg/day for 4 days, and TBI 400 cGy). A total of 248 patients (121 in the RIC group and 127 in the MAC group) were included in the analysis. No statistically significant difference was observed in 2-year OS (RIC group, 45.2 ± 5.0%; MAC group, 51.7 ± 5.2%; P = .541), nonrelapse mortality (NRM; RIC group, 28.7 ± 2.8% MAC group, 34.7 ± 4.6%; P = .368), and acute graft-versus-host disease (GVHD) (P = .171) or chronic GVHD (P = .605) at 1 year. The cumulative incidence of relapse (CIR) at 2 years was statistically significantly different between the 2 groups, however (RIC, 26.1 ± 2.6%; MAC, 14.2 ± 3.5%; P = .033). When PSM was applied to the study population, 42 case-control pairs were evenly matched. PSM analysis confirmed no statistically significant difference in 2-year OS (RIC, 49.0 ± 9.1%; MAC, 54.9 ± 7.7%; P = .718), NRM (RIC, 22.2 ± 2.3%; MAC, 33.3 ± 2.8%; P = .238), or CIR (RIC, 25.7 ± 2.6%; MAC, 9.5 ± 1.1%; P = .315) in the PSM pairs. Our findings demonstrate that after applying PSM, FBT 200 RIC conditioning has comparable OS, NRM, and CIR to FBT 400 MAC conditioning before allo-HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2016.08.030DOI Listing
December 2016

A systematic review of transfusion-associated graft-versus-host disease.

Blood 2015 Jul 30;126(3):406-14. Epub 2015 Apr 30.

Department of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada;

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare complication of blood transfusion. The clinicolaboratory features of TA-GVHD and the relative contributions of recipient and component factors remain poorly understood. We conducted a systematic review of TA-GVHD reports. The HLA relationship between donor and recipient was classified as D = 0 when no donor antigens were foreign to the recipient vs D ≥ 1 when ≥1 donor antigen disparity occurred. We identified 348 unique cases. Criteria for component irradiation were met in 48.9% of cases (34.5% immune-compromised, 14.4% related-donor), although nonirradiated components were transfused in the vast majority of these (97.6%). Components were typically whole blood and red cells. When reported, component storage duration was ≤10 days in 94%, and 23 (6.6%) were leukoreduced (10 bedside, 2 prestorage, and 11 unknown). Among 84 cases with HLA data available, the category of D = 0 was present in 60 patients (71%) at either HLA class I or II loci and was more common among recipients without traditional indications for component irradiation. These data challenge the historic emphasis on host immune defects in the pathogenesis of TA-GVHD. The dominant mechanism of TA-GVHD in both immunocompetent and compromised hosts is exposure to viable donor lymphocytes not recognized as foreign by, but able to respond against, the recipient.
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http://dx.doi.org/10.1182/blood-2015-01-620872DOI Listing
July 2015

Mycophenolate-based graft versus host disease prophylaxis is not inferior to methotrexate in myeloablative-related donor stem cell transplantation.

Am J Hematol 2015 May 8;90(5):392-9. Epub 2015 Apr 8.

Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Center, University of Toronto, Canada.

We retrospectively reviewed 242 patients who received related donor myeloablative peripheral blood hematopoietic cell transplantation. We compared patients who received mycophenolate (MMF)/cyclosporine (CSA) (n = 71), to historical controls who received methotrexate (MTX)/CSA (n = 172). There were no differences in overall survival, nonrelapse mortality, and relapse. The MMF/CSA group had significantly faster neutrophil and platelet engraftment: medians of 13 versus 18 days and 10 versus 14 days, respectively (P = 0.001). The cumulative incidence of acute graft versus host disease (GVHD) (Grades, 2-4) was significantly lower in the MMF/CSA group (45.1 vs. 74.4%, P < 0.001). The MMF/CSA group showed a lower incidence of skin (51.5 vs. 72.1%, P < 0.001) and liver acute GVHD (11.3 vs. 54.2%, P < 0.001) and a higher incidence of lung (42.2 vs. 19.0%, P = 0.045), eye (59.7 vs. 30.1%, P < 0.001), and mouth (72.8 vs. 56.4%, P = 0.001) chronic GVHD but only eye chronic GVHD was confirmed in propensity score matching (PSM) analysis. The incidence of cytomegalovirus (CMV) viremia was higher in the MMF/CSA group (55.8 vs. 39.6%, P < 0.001) but this was not confirmed in PSM analysis. MMF/CSA was identified as an independent favorable factor for acute GVHD (P < 0.001, hazard ratio, 0.41) but as a possible adverse risk factor for CMV viremia as this was not found to be statistically significant in PSM analysis. MMF/CSA in myeloablative matched related donor peripheral blood stem cell transplant is not inferior as GVHD prophylaxis in comparison with MTX/CSA and is associated with faster engraftment but a potentially higher risk of CMV viremia.
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http://dx.doi.org/10.1002/ajh.23955DOI Listing
May 2015

Modified EBMT Pretransplant Risk Score Can Identify Favorable-risk Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for AML, Not Identified by the HCT-CI Score.

Clin Lymphoma Myeloma Leuk 2015 May 5;15(5):e73-81. Epub 2014 Oct 5.

Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Introduction: Risk scores have been developed for allogeneic hematopoietic cell transplantation (HCT) outcomes, such as the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) and the modified European Group for Blood and Marrow Transplantation risk score (mEBMT) for acute leukemia. We investigated the influence of these scores for 350 patients who underwent transplantation for acute myeloid leukemia (AML).

Patients And Methods: The HCT-CI scores were grouped as 0 to 2 and ≥ 3 (231 and 119 patients, respectively) and the mEBMT scores as 0 to 2 and ≥ 3 (166 and 184 patients, respectively).

Results: Univariate analysis showed a significant association between the HCT-CI score and overall survival (OS) (P = .01), as did the mEBMT score (P = .002). The 5-year OS rate was 50% and 34% for a mEBMT score of 0 to 2 and ≥ 3, respectively. A subgroup of patients with a mEBMT score of 0 to 1 (n = 32) demonstrated a favorable OS of 75% at 5 years. This subgroup was younger (median age, 31 years), in first remission at transplantation, and had related donors. For the HCT-CI, the 5-year OS was 46% and 34% for a score of 0 to 2 and ≥ 3, respectively. Patients with an HCT-CI score of 0 (n = 94) had a 5-year OS of 44%. Multivariable analysis confirmed both the HCT-CI score and the mEBMT score, as previously grouped, as independent prognostic variables for both OS (P = .02 and P = .001, respectively) and nonrelapse mortality (NRM) (P = .01 and P = .003, respectively).

Conclusion: The results of the present study have demonstrated that the HCT-CI and mEBMT are both prognostic for OS and NRM in our cohort. However, the mEBMT score can identify a favorable-risk subgroup of patients not identifiable using the HCT-CI.
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http://dx.doi.org/10.1016/j.clml.2014.09.014DOI Listing
May 2015

A retrospective observational study of leucoreductive strategies to manage patients with acute myeloid leukaemia presenting with hyperleucocytosis.

Br J Haematol 2015 Feb 10;168(3):384-94. Epub 2014 Oct 10.

Division of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.

Acute myeloid leukaemia (AML) patients with hyperleucocytosis have higher early mortality, lower complete remission (CR) and overall survival (OS). Whether different pre-induction leucoreduction strategies can improve outcome is unknown. A single centre retrospective cohort study was conducted on AML patients with a white blood cell count (WBC) >100 × 10(9) /l between 1987 and 1997, and on all AML patients between 1998 and 2006, to determine (a) the effect of four different leucoreductive strategies (leukapheresis, hydroxycarbamide, leukapheresis and hydroxycarbamide or no pre-induction leucoreduction) on early (day 28) mortality, CR, and OS; and (b) whether a high presenting WBC remains a negative predictor of OS in patients surviving induction (first 28 d). In the 1998-2006 cohort (n = 702), higher WBC was associated with higher early mortality and lower OS but its effects were greatly diminished in patients who survived the first 28 d (Hazard Ratio 1·094 vs. 1·002). A WBC of 34·1 × 10(9) /l had the highest sensitivity (75·6%) and specificity (67·4%) for early mortality. None of the four leucoreduction strategies differed significantly in early mortality, CR, or OS in patients with WBC>100 × 10(9) /l (n = 166). The number of leucostatic signs was a significant predictor of early mortality (P < 0·0001) and OS (P = 0·0007). The results suggest that AML patients with hyperleucocytosis should be induced, if eligible, without pre-induction leucoreduction.
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http://dx.doi.org/10.1111/bjh.13146DOI Listing
February 2015

Incidence of erythropoietin antibody-mediated pure red cell aplasia: the Prospective Immunogenicity Surveillance Registry (PRIMS).

Nephrol Dial Transplant 2015 Mar 19;30(3):451-60. Epub 2014 Sep 19.

Janssen, Pharmaceutical Companies of Johnson & Johnson, Titusville, NJ, USA.

Background: Subcutaneous administration of Eprex(®) (epoetin alfa) in patients with chronic kidney disease (CKD) was contraindicated in the European Union between 2002 and 2006 after increased reports of anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA). The Prospective Immunogenicity Surveillance Registry (PRIMS) was conducted to estimate the incidence of antibody-mediated PRCA with subcutaneous administration of a new coated-stopper syringe presentation of Eprex(®) and to compare this with the PRCA incidence with subcutaneous NeoRecormon(®) (epoetin beta) and Aranesp(®) (darbepoetin alfa).

Methods: PRIMS was a multicentre, multinational, non-interventional, parallel-group, immunogenicity surveillance registry. Adults with CKD receiving or about to initiate subcutaneous Eprex(®), NeoRecormon(®) or Aranesp(®) for anaemia were enrolled and followed for up to 3 years. Unexplained loss or lack of effect (LOE), including suspected PRCA, was reported, with antibody testing for confirmation of PRCA.

Results: Of the 15 333 patients enrolled, 5948 received Eprex(®) (8377 patient-years) and 9356 received NeoRecormon(®)/Aranesp(®) (14 286 patient-years). No treatment data were available for 29 patients. Among 23 patients with LOE, five cases of PRCA were confirmed (Eprex(®), n = 3; NeoRecormon(®), n = 1; Aranesp(®), n = 1). Based on exposed time, PRCA incidence was 35.8/100 000 patient-years (95% CI 7.4-104.7) for Eprex(®) versus 14.0/100 000 patient-years (95% CI 1.7-50.6) for NeoRecormon(®)/Aranesp(®). The incidence of PRCA with Eprex(®) was not significantly different versus comparator ESAs (rate ratio: 2.56; 95% CI 0.43-15.31). An analysis based on observed time produced similar findings.

Conclusion: This large, prospective registry demonstrates that PRCA is rare with subcutaneous administration of either the new coated-stopper syringe presentation of Eprex(®), or NeoRecormon(®) or Aranesp(®).
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http://dx.doi.org/10.1093/ndt/gfu297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339685PMC
March 2015