Publications by authors named "Fotios V Michelis"

65 Publications

Association of Factors influencing selection of upfront hematopoietic cell transplantation versus non-transplant therapies in Myelofibrosis: Transplant decisions in MF.

Transplant Cell Ther 2021 Mar 30. Epub 2021 Mar 30.

Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

Background: Despite the curative potential of allogeneic hematopoietic cell transplantation (HCT) for myelofibrosis (MF), a significant number of patients do not undergo HCT. Factors influencing treatment preferences are not well studied in MF.

Objective(s): This study's objective was to identify patient, disease, and donor-related factors influencing HCT decision in MF. A secondary objective was to compare survival in patients who elected upfront HCT or non-transplant therapy.

Study Design: We conducted a retrospective chart review amongst patients meeting criteria for transplant indication, evaluating clinical characteristics, treatment preferences, and outcomes.

Results: Of the 183 study eligible patients <70 years, 129 (70%) developed an HCT indication. Age >60 years was significantly associated with higher rates of HLA-typing refusal (13/72 vs. 1/44, p = 0.02). Caucasian ethnicity was significantly associated with an increased rate of identifying well matched donors compared to non-Caucasian (75% vs. 48%, p = 0.02). Of the 69 patients with well-matched donors, 34 (49%) preferred not to pursue upfront HCT despite a transplant indication. Patient preferences for non-transplant therapies was the most common reason for declining HCT. We did not find any difference in survival between patients pursuing upfront HCT versus non-transplant therapies, although more patients were in remission in the HCT arm at the last follow-up.

Conclusion(s): Caucasian ethnicity patients were significantly more likely to identify a well-matched donor compared to non-Caucasian patients. Despite availability of a well-matched donor, a significant proportion of MF patients with transplant indication do not pursue HCT. Patient age, donor type and patient preferences play a major part in selection of upfront HCT. While a survival difference was not observed between upfront HCT versus non-transplant therapy, more patients in the HCT arm were in remission at the last follow up.
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http://dx.doi.org/10.1016/j.jtct.2021.03.027DOI Listing
March 2021

Predictors of outcomes of therapy-related acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.

Hematol Oncol Stem Cell Ther 2021 Mar 19. Epub 2021 Mar 19.

Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada. Electronic address:

Background/objective: Existing literature on allogeneic hematopoietic stem cell transplantation (allo-HSCT) in therapy-related acute myeloid leukemia (t-AML) is confounded by the inclusion of patients with secondary AML and t-MDS. We aim to report our 20-year experience of HSCT in t-AML.

Methods: We retrospectively reviewed patients with t-AML who underwent HSCT. Patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival (RFS), overall survival (OS), and predictors of outcomes.

Results: In total, 68 patients (59.9% female; median age, 56.5 years) underwent HSCT. Acute and chronic graft-versus-host disease (GVHD) occurred in 39 (57.4%) and 23 (33.8%) patients, respectively. Cumulative incidence of relapse, nonrelapse mortality, RFS, and OS at 2 years were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Significant predictors of reduced OS were presence of 11q23 rearrangement (hazard ratio [HR], 3.24), using induction regimens other than FLAG-Ida or 7 + 3 (HR, 3.65), haploidentical donors (HR, 3.48), Eastern Cooperative Oncology Group performance status 2 or higher (HR, 5.83), and using cyclosporine A-methotrexate as GVHD prophylaxis (HR, 2.41). A significant decrement in survival was seen with an increasing number of any of these prognostic factors.

Conclusion: Outcomes of t-AML are satisfactory after allo-HSCT. Patients with t-AML with good-risk karyotypes, good performance status, having HLA-matched donors, and receiving intensive induction regimens have better outcomes after HSCT.
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http://dx.doi.org/10.1016/j.hemonc.2021.03.003DOI Listing
March 2021

Prognostic impact of the adverse molecular-genetic profile on long-term outcomes following allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia.

Bone Marrow Transplant 2021 Mar 25. Epub 2021 Mar 25.

Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.

The impact of adverse risk genetic profiles on outcomes in acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (HCT) has not been fully elucidated. Accordingly, we have profiled somatic mutations at diagnosis using next-generation sequencing (NGS) in 178 AML patients who received allogeneic HCT. NGS revealed 598 somatic mutations in 165/178 patients (92.7%). Frequently mutated genes include DNMT3A, TET2, NPM1, RUNX1, IDH2, and FLT3. Commonly detected cytogenetic profiles include normal karyotype, trisomy 8, monosomal karyotype (MK), deletion 5, complex karyotype (CK), and monosomy 7. In univariate analyses, TP53 mutation, MK, CK, and monosomy 7 were associated with decreased overall survival (OS), relapse-free survival (RFS), and a higher relapse incidence (RI). We defined adverse molecular-genetic profile as harboring at least one of the molecular/genetic abnormalities of TP53 mutation, MK, CK, monosomy 7, and deletion 5. The patients harboring adverse molecular-genetic profile (n = 30) showed a lower 2-year OS (24.9% vs. 57.9%; p = 0.003), RFS (23.7% vs. 57.9%; p = 0.002), and higher RI (47.2% and 17.2%; p = 0.001) after HCT when compared to patients without those lesions. Multivariate analysis confirmed adverse molecular-genetic profile as an independent prognostic factor, associated with decreased OS (HR 2.19), RFS (HR 2.23), and higher RI (HR 2.94).
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http://dx.doi.org/10.1038/s41409-021-01255-4DOI Listing
March 2021

Moderate-severe grade of chronic graft versus host disease and younger age (less than 45 years old) are risk factors for avascular necrosis in adult patients undergoing allogeneic hematopoietic cell transplantation.

Ann Hematol 2021 May 12;100(5):1311-1319. Epub 2021 Mar 12.

Hans Messner Allogeneic Blood and Marrow Transplant Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 700 University Ave., Toronto, Ontario, M5G 1Z5, Canada.

Avascular necrosis (AVN) is a debilitating complication of allogeneic hematopoietic cell transplantation (HCT). A retrospective review of 845 patients who underwent HCT was conducted. Cumulative incidence of AVN was 6.3% at 4 years. The following risk factors were significantly associated with AVN risk on univariate analysis: age < 45 (p=0.004), moderate to severe chronic GvHD (p<0.001), reduced intensity conditioning (p=0.02), and a diagnosis of acute leukemia (p=0.045). Multivariate analysis confirmed two risk factors: younger age (<45 years), 9.0% vs 4.4% (p=0.011, hazard ratio (HR) 2.134), and moderate-severe chronic GvHD, 15.4% vs 2.1% (p<0.001, HR 4.950). A risk score model was generated assigning a score to each risk factor. A score of 1 was assigned to moderate-severe GvHD or those with age <45. Total score was calculated, thus dividing patient into three groups: low (score 0, n=349, 41.3%), intermediate (score 1, n=379, 44.9%), and high risk (score 2; n=116, 13.7%). This risk score could stratify the patients according to AVN risk (p<0.001). The risk of AVN was 1.5% in the low risk, 6.2% in the intermediate risk, and 20.8% in the high risk groups. Moderate-severe chronic GvHD and younger age (<45 years) are key risk factors for AVN following allogeneic HCT.
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http://dx.doi.org/10.1007/s00277-021-04480-5DOI Listing
May 2021

Subcutaneous immunoglobulin in allogeneic hematopoietic cell transplant patients: A prospective study of feasibility, safety, and healthcare resource use.

Hematol Oncol Stem Cell Ther 2021 Feb 23. Epub 2021 Feb 23.

Hans Messner Allogeneic Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: We evaluated feasibility, safety, and total resource use of subcutaneous immunoglobulin (SCIG) in a pilot study of patients who underwent allogeneic hematopoietic cell transplant (HCT) over a 6-month period.

Methods: A total of 20 eligible patients were treated with SCIG at 0.1 g/kg/week for up to 6 months. Patients were matched to 20 concurrent intravenous immunoglobulin (IVIG) controls. Clinical outcomes measured included adverse reactions, healthcare resource use, patient satisfaction, and quality of life (QOL). (ClinicalTrials.gov Identifier: NCT03401268.) RESULTS: Groups were comparable in terms of age, weight, sex, transplant indication, donor type, and conditioning intensity. All 20 IVIG patients completed 6 consecutive months of therapy compared with 13/20 (65%) SCIG patients. There were no adverse reactions in IVIG patients, compared with six (30%) SCIG patients. All adverse reactions in SCIG patients were grade I, transient, and required no medical intervention. Median overall cost per patient was lower with SCIG than with IVIG ($9,756 vs. $13,780, p = .046). Among patients who completed 6 months of SCIG, median preference and satisfaction scores were 100%. Over the 6-month period, QOL scores remained stable in SCIG patients.

Conclusions: In a subgroup of patients, SCIG was associated with high patient satisfaction and a reduction in total healthcare costs compared with IVIG in a cohort of HCT patients.
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http://dx.doi.org/10.1016/j.hemonc.2021.01.001DOI Listing
February 2021

Comparison of the Prognostic Ability of the HCT-CI, the Modified EBMT, and the EBMT-ADT Pre-transplant Risk Scores for Acute Leukemia.

Clin Lymphoma Myeloma Leuk 2021 Feb 3. Epub 2021 Feb 3.

Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Electronic address:

Background: Allogeneic hematopoietic cell transplantation (HCT) outcomes may be predicted by published risk scores; however, the ideal system has not been identified for acute leukemias.

Patients And Methods: We retrospectively examined the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), modified European Group for Blood and Marrow Transplantation (mEBMT), EBMT-Alternating Decision Tree (ADT), and others on 231 patients with acute leukemia.

Results: Acute myeloid leukemia was diagnosed in 200 patients, and acute lymphocytic leukemia was diagnosed in 31 patients. For HCT-CI, patients were grouped as 0 to 1, 2 to 3, and > 3. For mEBMT, patients were grouped as 0 to 2, 3, and > 3. For EBMT-ADT, the 100-day mortality was calculated and grouped as ≤ 4.1%, 4.1% to 11.5%, and > 11.5%. Higher HCI-CI demonstrated inferior overall survival (P = .04; c-statistic, 0.57), whereas mEBMT and EBMT-ADT did not stratify well. A new weighted score was developed that assigned 1 point for age ≥ 60 years, acute lymphocytic leukemia diagnosis, mismatch unrelated or haploidentical donor, cardiovascular comorbidity, and pre-transplant diabetes, whereas arrhythmia received 2 points. The new weighted score assigned 0 points to 88 (38%), 1 to 2 points to 121 (52%) and ≥ 3 points to 22 (10%) patients, and demonstrated improved prognostic capability compared with the other scores (P = .0001; c-statistic, 0.61).

Conclusions: The HCT-CI stratifies patients with leukemia for overall survival but is inferior to our single-center score, which is influenced by cardiac comorbidity and arrhythmia. Differences in pre-transplant risk scores may be related to different transplant practices.
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http://dx.doi.org/10.1016/j.clml.2021.01.022DOI Listing
February 2021

Refined hepatic grading system in chronic graft-versus-host disease improves prognostic risk stratification of long-term outcomes.

Eur J Haematol 2021 Apr 25;106(4):508-519. Epub 2021 Jan 25.

Department of Medical Oncology and Hematology, Hans Messner Allogeneic Stem Cell Transplant Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Objectives: Hepatic grading systems for categorizing severity in chronic graft-versus-host disease (cGvHD) were determined arbitrarily, leading us to initiate the present study to provide objective evidence for the determination of optimal cutoff values and devise a hepatic grading system to predict prognosis.

Methods: Of 842 patients who received allogeneic hematopoietic stem transplant (HCT), 336 patients diagnosed with cGvHD were evaluated for overall survival (OS) and non-relapse mortality (NRM) after cGVHD development. Multiple statistical parameters were evaluated to define optimal cutoff values of liver profile, including negative predictive value (NPV), positive predictive value (PPV), accuracy, and p-values as measures of risk stratification power.

Results: We found that alkaline phosphatase (ALP) ≥ 146 IU/L (NPV: 83.4%; PPV: 32.8%; accuracy: 52.7%) and bilirubin ≥ 14 µmol/L (NPV: 81.8%; PPV: 39.4%; accuracy 68.1%) significantly correlated with OS. We developed a refined hepatic cGvHD grading score (RHS), stratifying patients into a low-RHS group with RHS score 0, OS at 3 years (n = 162) to 80.5%, compared to high-RHS group with score 1-2 (n = 172) 62.7%. Regarding NRM, score 0 segregated NRM at 3 years to 11.9%, compared with score 1-2 19.6%, P = .1.

Conclusions: Refined hepatic score is promising for stratifying patients with cGVHD and liver involvement according to long-term outcomes.
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http://dx.doi.org/10.1111/ejh.13576DOI Listing
April 2021

Post-transplant ferritin level predicts outcomes after allogeneic hematopoietic stem cell transplant, independent from pre-transplant ferritin level.

Ann Hematol 2021 Mar 7;100(3):789-798. Epub 2021 Jan 7.

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

Allogeneic hematopoietic stem cell transplantation (HCT) is associated with significant morbidity and mortality. Elevated pre-transplant ferritin level (ferritin) is reported to be associated with increased mortality following HCT. The present study attempted to determine whether post-transplant ferritin level (ferritin) is associated with outcomes post-HCT, especially in the subgroups which developed acute or chronic graft-versus-host disease (GVHD). Out of 229 patients with serum ferritin level measured post-HCT, median ferritin was 2178 ng/mL. Patients were stratified into low- or high-risk groups using recursive partitioning, based on ferritin (≤ 3169 vs > 3169 ng/mL) and ferritin (≤ 669 vs > 669 ng/mL). Compared to the low ferritin group, the high ferritin group had lower 3-year overall survival (OS) (40.0% vs 66.7%, p < 0.001) and higher non-relapse mortality (NRM) (48.6% vs 17.8%, p < 0.001), but no difference in relapse (10.5% vs 19.7%, p = 0.079). Multivariate analysis confirmed ferritin as an independent prognostic factor for OS (p = 0.001, HR = 2.323) and NRM (p < 0.001, HR = 3.905). However, ferritin did not stratify well for OS or NRM. Ferritin was also found to be an independent prognostic marker for OS and NRM in the subgroups which developed GVHD. In our cohort, high ferritin levels were significantly associated with decreased OS and increased NRM independent of ferritin or GVHD. Additional studies including larger sample sizes and prospective investigation are warranted to clarify the prognostic significance and pathophysiology of pre- and post-transplant hyperferritinemia.
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http://dx.doi.org/10.1007/s00277-020-04363-1DOI Listing
March 2021

Comorbidity profile of adult survivors at 20 years following allogeneic hematopoietic cell transplantation.

Eur J Haematol 2021 Feb 17;106(2):241-249. Epub 2020 Nov 17.

Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Numerous chronic medical conditions and complications can arise following allogeneic hematopoietic cell transplantation (HCT) that may have a negative impact on survival and quality of life.

Objective: The purpose of the present study was to review the comorbidities of a single-center cohort of allogeneic HCT recipients that survived 20 years postallogeneic transplantation.

Methods: We retrospectively investigated 172 patients that underwent allogeneic HCT at the Princess Margaret Cancer Centre between 1979 and 1998 and who survived at least 20 years post-HCT.

Results: The most frequent individual comorbidities documented were dyslipidemia (29%), hypertension (31%), osteoporosis (15%), hypothyroidism (15%), and depression/anxiety (13%). Follow-up data following the 20-year mark were available for 135 patients, overall survival (OS) of that group at 5 and 10 years was 94% and 90%, respectively. When grouped by the number of concurrent comorbidities, there was a significant difference in OS between the groups with 0-1, 2-3, and ≥4 comorbidities (P = .01).

Conclusions: Evidently, long-term allogeneic HCT recipients may develop a number of comorbidities that negatively influence survival even past the 20-year post-transplant mark. These findings warrant the continuous long-term medical follow-up of allogeneic transplant patients, regardless of age or time that has lapsed post-HCT.
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http://dx.doi.org/10.1111/ejh.13542DOI Listing
February 2021

Fresh vs. frozen allogeneic peripheral blood stem cell grafts: A successful timely option.

Am J Hematol 2021 02 10;96(2):179-187. Epub 2020 Nov 10.

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

Cryopreservation of grafts has been established in autologous and cord blood transplantation, yet there is little experience regarding the effect of cryopreservation with sibling and unrelated grafts. We evaluated the effect of cryopreservation of grafts on allogeneic transplant outcomes using related, unrelated and haploidentical donors, including 958 patients, age 18-74 years (median 55) and using PBSC for various hematologic malignancies. Fresh grafts were received by 648 (68%) patients, 310 (32%) received cryopreserved. There was no difference between fresh vs cryopreserved grafts for neutrophil engraftment (P = .09), platelet engraftment (P = .11), graft failure (5.6% vs 6.8%, P = .46) and grade II-IV acute graft-vs-host disease (GVHD) (P = .71), moderate/severe chronic GVHD was observed in 176 (27%) vs 123 (40%) patients, respectively (P < .001). Multivariable analysis demonstrated no difference between fresh vs cryopreserved for OS (P = .39) and CIR (P = .08) while fresh grafts demonstrated borderline increased NRM (HR 1.27, 95% CI 1.02-1.59, P = .04). Of note, for patients with no or mild chronic GVHD, CIR was less for fresh compared to cryopreserved (HR = 0.67 for fresh, 95% CI 0.48-0.92, P = .01). We conclude there were no differences in engraftment and survival between fresh and cryopreserved grafts for allogeneic HCT, thus establishing cryopreservation to be a safe option for allogeneic HCT.
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http://dx.doi.org/10.1002/ajh.26033DOI Listing
February 2021

Outcomes of adult patients with acute myeloid leukemia and unsuccessful cytogenetic analysis undergoing allogeneic hematopoietic stem cell transplantation.

Hematol Oncol Stem Cell Ther 2020 Oct 8. Epub 2020 Oct 8.

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

Objective/background: Unsuccessful cytogenetic (US) analysis at baseline has been reported to be a poor prognostic feature in patients with acute myeloid leukemia (AML). We conducted this study to examine the prognostic impact of UC/inconclusive cytogenetic analysis on outcomes in patients with AML undergoing allogeneic hematopoietic stem cell transplantation (Allo HSCT).

Methods: We retrospectively analyzed all adults undergoing Allo HSCT for AML from January 2011 to August 2019. Patients with any documented cytogenetic abnormalities were excluded. Baseline characteristics and transplant outcomes were compared between patients with normal cytogenetics and those with UC.

Results: Overall, 243 AML patients (median age, 55 years; 55.1% female) were included. UC were reported in 79 patients, whereas 164 patients had a normal karyotype. The two groups were similar to each other in terms of baseline demographics, treatment received, and transplant related variables. There was no difference between patients with UC and normal cytogenetics in terms of relapse-free survival (66 months vs. 42 months, p = .53) or overall survival (OS; 77 months vs. 76 months, p = .72). Survival parameters remained similar even in subgroup analysis based on NPM1 and FLT3 mutation status. Significant predictors of OS after Allo HSCT in AML patients with UC were increased age at time of Allo HSCT (hazard ratio [HR] = -1.049; 95% confidence interval [CI], 1.005-1.095), favorable (NPM1/FLT3) mutation profile (HR = 0.11; 95% CI, 0.01-0.84), neutrophil engraftment < 17 days, and absence of chronic graft-versus-host disease (HR = 3.27; 95% CI, 1.20-8.60).

Conclusion: Outcomes after Allo HSCT are comparable between AML patients with UC analysis and patients with normal cytogenetics even after stratification based on molecular risk factors. Allogeneic Allo HSCT may mitigate the poor prognosis of UC analysis in patients with AML.
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http://dx.doi.org/10.1016/j.hemonc.2020.09.001DOI Listing
October 2020

Prolactin, a potential biomarker for chronic GVHD activity.

Eur J Haematol 2021 Feb 26;106(2):158-164. Epub 2020 Oct 26.

Section of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Introduction: The polypeptide prolactin (PRL) is a peptide hormone and a cytokine mostly secreted from the anterior pituitary gland. PRL is also synthesized in extra pituitary tissues including thymocytes and T lymphocytes. Considering the need for chronic GVHD (cGVHD) biomarkers, we explored the relationship between hyperprolactinemia and active cGVHD in a cohort of long-term post-alloHCT survivors.

Methods: Three-hundred sixteen adults underwent alloHCT between 2010 and 2016, survived more than 1 year and were included. All patients underwent a regular annual assessment that includes a hormone profile with serum PRL levels.

Results: Overall, 236 (74.7%) patients had cGVHD, and in 199 (63%), the grade was moderate or severe. Sixty-five (21%) recipients had active cGVHD at the time of the annual evaluation, and hyperprolactinemia was documented in 63 (19.9%) patients. Hyperprolactinemia correlated with cGVHD activity (Odds Ratio 6.9 (95% CI; 3.6-13.1); P < .001) in the multivariate analysis. In conclusion, patients with hyperprolactinemia were 6.4 times more likely to have active cGVHD in comparison with those patients with normal levels of PRL (P < .001).

Conclusion: Prolactin may serve as a biomarker for cGVHD activity. Further studies are required to confirm these findings, and to explore if hyperprolactinemia has an impact on cGVHD severity and prognosis.
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http://dx.doi.org/10.1111/ejh.13531DOI Listing
February 2021

Pilot prospective study of Frailty and Functionality in routine clinical assessment in allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Jan 30;56(1):60-69. Epub 2020 Jun 30.

Department of Medicine, Section of Medical Oncology and Hematology, University of Toronto, Toronto, ON, Canada.

A Frailty and Functionality evaluation for alloHCT was implemented using existing resources. We describe the implementation of this evaluation across all ages and at first consultation, and correlate results with posttransplant outcomes in 168 patients. The evaluation consists of: Clinical Frailty Scale (CFS), Instrumental Activities of Daily Living (IADL), grip strength (GS), timed up and go test (TUGT), self-rated health question (SRH), Single question of Falls, albumin and C-Reactive Protein (CRP) levels. Median time to perform the evaluation was 5-6 min. Median age was 58 years (range: 19-77) and median follow-up was 5.3 months. TUGT > 10 s (HR 2.92; p = 0.003), raised CRP (HR 4.40; p < 0.001), and hypoalbuminemia (HR 2.10; p = 0.043) were significant risk factors for worse overal survival (OS). CFS ≥ 3 (HR 3.11; p = 0.009), TUGT > 10 s (HR 3.47; p = 0.003), GS (HR 2.56; p = 0.029), SRH ( 10 s and raised CRP were significant predictors for worse OS and NRM. SRH (
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http://dx.doi.org/10.1038/s41409-020-0979-1DOI Listing
January 2021

Clinical prevalence and outcome of cardiovascular events in the first 100 days postallogeneic hematopoietic stem cell transplant.

Eur J Haematol 2021 Jan 13;106(1):32-39. Epub 2020 Oct 13.

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

Introduction: Recent advances in allogeneic hematopoietic stem cell transplant (HSCT) have allowed us to offer HSCT to older, advanced disease patients with more co-morbidities. Cardiovascular toxicity post-transplant is a major concern due to the increased risk of mortality. Few studies have examined the prevalence of CV events including CAD (MI, angina, PCI, CABG, CHF, arrhythmias), HTN, stroke/TIA, and death in the first 100 days post-transplant.

Patients: We assessed the impact of pretransplant MUGA results in predicting postallogeneic HSCT CV events and overall survival in the first 100 days, and whether or not transient anthracycline-induced cardiomyopathy or cumulative anthracycline dose affected overall survival. This retrospective, cohort study included 665 patients with a median age of 52 years who underwent HSCT from 2009 to 2015.

Results: The most frequent CV event in the first 100 days post-HSCT was arrhythmia seen in 2.9% of patients followed up by CHF (12.3%), MI (9%), and angina (8%). Two patients had PCI, and both survived the first 100 days. Cardiovascular risk factors predict for a poor MUGA scan but not survival. Higher dose anthracycline pretransplant predicted for a poor outcome.

Conclusion: A history of CV disease, MI, or CAD was the most important predictive of CV events, P-value = .00002. 88.6% survived the first 100 days. Patients with an EF < 50% had a significant likelihood of having a CV event compared to patients with an EF > 60% (OR = 5.3, 95% CI [1.6-18.1], P = .0219). Cumulative anthracycline dose did not have a significant impact on overall survival.
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http://dx.doi.org/10.1111/ejh.13482DOI Listing
January 2021

Post-Transplant Cyclophosphamide Combined with Anti-Thymocyte Globulin as Graft-versus-Host Disease Prophylaxis for Allogeneic Hematopoietic Cell Transplantation in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Acta Haematol 2021 19;144(1):66-73. Epub 2020 May 19.

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

Background: Allogeneic hematopoietic cell transplantation (HCT) is curative for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but with significant non-relapse mortality (NRM) and relapse. We compared the combination of anti-thymocyte globulin (ATG; 4.5 mg/kg) and post-transplant cyclophosphamide (PTCy; 50 mg/kg on day +3 and +4) with other graft-versus-host disease (GvHD) prophylaxis regimens used for these patients.

Methods: We retrospectively analyzed 159 patients, aged 22-73 (median 56) years, having undergone transplantation for high-risk AML (n = 120) or MDS (n = 39). The donors were matched related (33%), unrelated (55%) and haploidentical (12%). Almost all patients used peripheral blood stem cells. Conditioning was myeloablative (34%) or reduced intensity (66%). ATG + PTCy was used in 69 patients (43%), and other GvHD prophylaxis regimens in 90 patients (57%).

Results: Grade III-IV acute GvHD occurred in 4% of the ATG + PTCy patients versus 20% of those using other regimens (p = 0.004), and chronic GvHD in 19% of the ATG + PTCy patients versus 41% of those using other regimens (p = 0.003). Two-year GvHD-free relapse-free survival (GRFS) was 30% with ATG + PTCy versus 18% with other regimens (p = 0.04). Multivariable analysis demonstrated that while ATG + PTCy had no significant influence on overall survival, cumulative incidence of relapse or NRM, there was a significant influence on GRFS in favor of ATG + PTCy (HR = 0.69, 95% CI 0.45-0.99, p = 0.04).

Conclusions: We conclude that the ATG + PTCy combination significantly improved GRFS in allogeneic HCT for high-risk AML and MDS without influencing other outcomes.
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http://dx.doi.org/10.1159/000507536DOI Listing
March 2021

Less Is More: Superior Graft-versus-Host Disease-Free/Relapse-Free Survival with Reduced-Intensity Conditioning and Dual T Cell Depletion in Acute Myelogenous Leukemia.

Biol Blood Marrow Transplant 2020 08 16;26(8):1511-1519. Epub 2020 May 16.

Hans Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Hematology Department, Institut Català d'Oncologia-Hospitalet, IDIBELL, Barcelona, Spain.

In this study, we compared the outcomes of patients with acute myelogenous leukemia (AML) in complete remission treated with myeloablative conditioning (MAC) and those treated with reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HCT). In addition, we explored the efficacy of dual T cell depletion using anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) for the prevention of graft-versus-host disease (GVHD) in patients undergoing RIC allo-HCT. Our study cohort comprised 356 adults with AML in complete remission who underwent allo-HCT between 2013 and 2018. One hundred eleven patients (31.2%) received a MAC regimen, and 245 (68.8%) received an RIC regimen. One hundred seventy-one of the patients who received an RIC regimen (68.4%) received ATG, PTCy, and cyclosporine (ATG-PTCY-CsA) for GVHD prophylaxis in accordance with our institutional protocol. Data were collected retrospectively and updated in July 2019. With a median follow-up of 14.5 months (range, 0 to 76 months), 161 patients (45.2%) died, and 66 (18.5%) relapsed. Two-year overall survival (OS), relapse-free survival (RFS), and GVHD-free/RFS (GRFS) were 55%, 52.6%, and 35%, respectively. The intensity of the conditioning regimen, with or without ATG-PTCY-CsA, did not have a significant impact on OS and RFS. However, RIC in combination with ATG-PTCY-CsA was associated with a significantly lower cumulative incidence of acute GVHD and chronic GVHD. The use of RIC with ATG-PTCy-CsA was a significant predictor for higher GRFS secondary to the reduction of clinically relevant GVHD (P= .0001). In patients with AML, RIC allografts and dual T cell modulation with ATG and PTCy led to superior GRFS. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity using RIC, may result in better long-term quality of life for allo-HCT recipients.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.021DOI Listing
August 2020

Post-transplant cyclophosphamide combined with anti-thymocyte globulin for graft-vs-host disease prophylaxis improves survival and lowers non-relapse mortality in older patients undergoing allogeneic hematopoietic cell transplantation.

Ann Hematol 2020 Jun 7;99(6):1377-1387. Epub 2020 May 7.

Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

Graft-versus-host disease (GVHD) represents a major contributor to morbidity and mortality in recipients of allogeneic hematopoietic cell transplants (HCT). Several strategies exist for GVHD prophylaxis and include post-transplant cyclophosphamide (PTCY) and anti-thymocyte globulin (ATG). While several groups have described the use of PTCY in younger patients, there is a paucity of data about the efficacy of PTCY in older individuals, particularly when combined with ATG. We investigated the effect of PTCY and ATG combination on transplant outcomes in older patients at Princess Margaret Cancer Centre, Toronto, Canada. Compared to those patients who received other forms of GVHD prophylaxis, individuals who received ATG-PTCY combination had higher 2-year overall survival (OS), 57% (95% confidence interval, 44-69) vs 37% (26-49), P = 0.02; higher 2-year graft-vs-host- and relapse-free survival (GRFS), 27% (17-39) vs 12% (6-21), P = 0.01; lower 2-year non-relapse mortality (NRM), 21% (12-32) vs 45% (33-56), P = 1.00 × 10; lower 100-day incidence of grade 2-4 acute GVHD (aGVHD), 11% (5-21) vs 28% (18-39), P = 0.02; and lower 100-day incidence of grade 3-4 aGVHD, 0% vs 7% (3-15), P = 0.02 without an increase in the 2-year cumulative incidence of relapse (CIR), 31% (20-43) vs 21% (12-32), P = 0.14. Therefore, in older HCT recipients, use of PTCY combined with ATG is associated with improved OS, lower NRM, decreased risk of aGVHD, and improved GRFS without a significant increase in relapse risk. Therefore, the PTCY with ATG combination represents an effective strategy for GVHD prophylaxis in older allogeneic HCT recipients.
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http://dx.doi.org/10.1007/s00277-020-04033-2DOI Listing
June 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

Outcomes of therapy-related acute lymphoblastic leukemia in adults after allogeneic stem cell transplantation.

Eur J Haematol 2020 Jul 18;105(1):24-29. Epub 2020 Mar 18.

Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada.

Introduction: Therapy-related acute lymphoblastic leukemia (t-ALL) is an increasingly recognized subset of therapy-related acute leukemia. There are limited data on the role of allogeneic hematopoietic stem cell transplantation (HSCT) in t-ALL. Recent reports suggest comparable outcomes of t-ALL with de novo ALL after HSCT.

Patients And Methods: We retrospectively reviewed all patients of t-ALL who underwent HSCT at our center. Patients were analyzed for prior malignancy, therapy, time to diagnosis of t-ALL, clinical, laboratory characteristics, transplant details, relapse-free survival (RFS), and overall survival (OS).

Results: Eighteen patients (M:F ratio 1:1; Median age 44 years) underwent HSCT for t-ALL. Median latent period from primary malignancy to t-ALL was 44.8 months. 11q23 rearrangement and t(9;22) were present in 33.3% and 22.2% patients, respectively. Stem cell donors were matched related, matched unrelated, and haploidentical in 27.8% (n = 5), 55.6% (n = 10), and 16.7% (n = 3) patients, respectively. Five patients died before D+ 100 (27.8%). Estimated 2-year RFS and OS were 47.1% and 51.8%, respectively. We did not find any pretransplant and post-transplant risk factors that were predictive of improved OS or RFS after multivariate analysis.

Conclusions: Allogeneic HSCT outcomes in t-ALL were comparable to HSCT outcomes in de novo ALL. Multicenter studies with more patients and longer follow-up may provide factors affecting outcome and survival.
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http://dx.doi.org/10.1111/ejh.13403DOI Listing
July 2020

Dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning allo-HSCT results in very low rates of GVHD.

Bone Marrow Transplant 2020 09 5;55(9):1773-1783. Epub 2020 Feb 5.

Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology. Princes Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

The efficacy of posttransplant cyclophosphamide (PTCy) and antithymocyte globulin (ATG) in controlling GVHD has been previously reported. We aim to study the safety and efficacy of the use of dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning regimen allo-HSCT in 270 patients with hematological malignancies. Median follow-up was 12.7 months. Nineteen percent of patients received grafts from a matched related donor, 46% from 10/10 matched unrelated donors (MUD), 16% from 9/10 MUD and 19% from haploidentical donors. Graft failure rate was 9%. CMV and EBV reactivation rates were 58 and 64%. The cumulative incidence of grade II-IV and III-IV acute GVHD at day + 100 was 20.1% and 4.6%, respectively. The CI of moderate/severe chronic GVHD at 1 year was 12.4%. There were no differences in the incidence of GVHD according to donor type. One-year OS, RFS, NRM, CIR, and GVHD-free/RFS respectively were 65.2%, 56.9%, 22.7%, 20.3%, and 47.6%. Higher disease-risk index and worse Karnofsky performance status were significant factors for poor outcomes. In conclusion, the use of T-cell dual depletion with ATG and PTCy results in very low rates of acute and chronic GVHD and acceptable relapse rates and NRM.
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http://dx.doi.org/10.1038/s41409-020-0813-9DOI Listing
September 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

Allogeneic stem cell transplant in myelodysplastic syndrome-factors impacting survival.

Eur J Haematol 2020 Feb 2;104(2):116-124. Epub 2019 Dec 2.

Princess Margaret Cancer Centre, Toronto, ON, Canada.

Objectives: The primary aim of this study was to evaluate survival outcomes following allo-HCT in myelodysplastic syndrome (MDS), and the secondary aim was to study variables impacting survival.

Methods: This analysis describes patient characteristics, treatment, and outcomes in 125 consecutive adult patients with MDS transplanted from 2005 to 2018.

Results: The median age was 61 years, and median follow-up in patients alive at last follow-up was 29 months. The 2-year OS and RFS were 39% (95%CI 30%-48%) and 35.3% (95% CI: 27%-44%), respectively. Transfusion dependence, high-risk cytogenetics, and high serum ferritin were independent risk factors for death. The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 2 years were 23% and 41.6%, respectively. High serum ferritin was significantly associated with NRM. There was no association between the percentage of bone marrow blasts (either at diagnosis or at pretransplant evaluation), on relapse or survival. Induction chemotherapy did not offer any survival advantage in MDS RAEB-2 patients compared to cytoreduction with azacytidine alone.

Conclusion: Our results highlight the importance of karyotype on survival after allo-HCT and identify serum ferritin and transfusion dependence as important surrogate markers of outcome. In addition, our results demonstrate the efficacy of azacytidine for pretransplant cytoreduction.
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http://dx.doi.org/10.1111/ejh.13353DOI Listing
February 2020

My jamais vu in post allogeneic hematopoietic cell transplant: a review on secondary hemophagocytosis in adults.

Bone Marrow Transplant 2020 05 14;55(5):867-872. Epub 2019 Oct 14.

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

Post allogenic hematopoietic cell transplant (HCT) hemophagocytic lymphohistiocytosis (HLH) is an aggressive disease with unknown etiology. It has a poorly understood pathophysiology and poor outcome if untreated early. It's a state of hypercytokinemia. There are many proposed diagnostic criteria for Post HCT HLH. It usually occurs early in the first 2-6 weeks after allogeneic HCT but can present late. The incidence is highest among cord blood transplant compared with other sources of stem cells with a higher incidence in HLA mismatch donors. Post HCT HLH has a marked low survival rate, when compared with Non-HLH post HCT patients and specifically poor outcome is associated in patients with liver dysfunction, graft failure, and those with endothelial complications. Steroid is the mainstay treatment which can be followed up by cyclosporine and etoposide though an optimal therapy is not known. Intravenous immunoglobulin (IVIg) has been tried in virus associated HLH. Second bone marrow transplant is a rescue procedure in patient with HLH due to graft failure, though a very careful selection of individual patients is mandatory. It has been recently found that etoposide based conditioning regimen may reduce HLH post HCT. A prospective study on post HCT HLH are needed to evaluate this unrecognized condition.
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http://dx.doi.org/10.1038/s41409-019-0711-1DOI Listing
May 2020

Impact of CD34+ cell dose on reduced intensity conditioning regimen haploidentical hematopoietic stem cell transplantation.

Eur J Haematol 2020 Jan 6;104(1):36-45. Epub 2019 Oct 6.

Section of Medical Oncology and Hematology, Department of Internal Medicine, University of Toronto, ON, Canada.

Objectives: Haploidentical hematopoietic stem cell transplant (haplo-SCT) has been associated with higher rates of graft rejection, and a higher dose of CD34+ cell dose is frequently requested. We aim to explore the impact of CD34+ cell dose in peripheral blood stem cell (PBSC) grafts using reduced intensity conditioning (RIC) in haplo-SCT.

Methods: Sixty-eight consecutive haplo-SCT in adult patients were included. Graft-vs-host disease (GVHD) prophylaxis consisted on ATG, PTCy, and CsA. The cohort was divided in two groups using CD34+ dose of ≥ 9 × 10 CD34+/Kg as cutoff point. Median follow-up was 8.9 months.

Results: Median cell dose infused was 9.32 × 10 CD34+/Kg. Forty (58.8%) recipients received grafts with CD34+ cells ≥9 × 10 /kg. The infusion ≥ 9 × 10 CD34+/Kg cell dose had a negative impact in overall survival (P = .03) after adjusting for age at transplant. The cumulative incidence of acute GVHD and graft failure were not significantly influenced per CD34+ cell dose. Only four recipients had grade III aGVHD, and all of them received grafts with a CD34+ cell dose ≥ 9 × 10 .

Conclusion: In RIC haplo-SCT, recipients may not benefit from PBSC grafts with a CD34+/kg cell dose higher than 9 × 10 cells/kg, as it can have an adverse impact in post-transplant outcome.
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http://dx.doi.org/10.1111/ejh.13332DOI Listing
January 2020

Reduced-intensity conditioning allogeneic transplant with dual T-cell depletion in myelofibrosis.

Eur J Haematol 2019 Dec 30;103(6):597-606. Epub 2019 Sep 30.

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

Background: There remains a significant mortality in recipients with MF who undergo allogeneic stem cell transplant (allo-HSCT). The combination of antithymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) provides good control of graft-versus-host disease (GVHD) when peripheral blood stem cell grafts are used.

Methods: We report the outcome of 37 recipients with myelofibrosis who underwent reduced-intensity conditioning (RIC) allo-HSCT with ATG and PTCy. Median follow-up was 16.4 months.

Results: Nine (24.3%) recipients received 10/10 MRD grafts, 17 (45.9%) 10/10 MUD grafts, 4 (10.8%) 9/10 MUD grafts, and 7 (18.9%) haploidentical donor grafts. Six (16.3%) patients had graft failure. The cumulative incidence of grade II-IV and grade III-IV aGVHD at day +100 and moderate/severe chronic GVHD at 1 year was as follows: 13.5%, 5.4%, and 17%. There were no deaths secondary to GVHD. One-year overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and GVHD-free/RFS (GRFS) were respectively 74.4%, 71.3%, 23%, and 43.3%. Those recipients who had worse KPS ≤ 80% had worse OS and RFS.

Conclusion: RIC allo-HSCT with ATG and PTCy results in high OS and RFS in patients with myelofibrosis and absence of mortality secondary to GVHD. Further investigations are required to reduce NRM and graft failure rates.
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http://dx.doi.org/10.1111/ejh.13327DOI Listing
December 2019

Reduced intensity allogeneic stem cell transplant with anti-thymocyte globulin and post-transplant cyclophosphamide in acute myeloid leukemia.

Eur J Haematol 2019 Nov 9;103(5):510-518. Epub 2019 Sep 9.

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

Objectives: We aimed to study the efficacy of reduced intensity conditioning (RIC) allo-HSCT combined with anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in AML.

Methods: One hundred forty-seven patients were included. All patients underwent unmanipulated peripheral blood stem cell RIC allo-HSCT. Median follow-up was 12.8 months (range 0.5-39).

Results: Median age was 58 years. Twenty-nine (20%) recipients received 10/10 MRD grafts, 69 (47%) 10/10 MUD grafts, 20 (13.6%) 9/10 MMUD, and 29 (20%) haploidentical grafts. The cumulative incidence of grade II-IV and III-IV acute GVHD at day +100, and moderate/severe chronic GVHD at 1-year were as follow: 14.3%, 1.4%, and 8.3%. There were no significant differences according to donor type (P = .46) and cumulative incidence of GVHD. One-year overall survival (OS), relapse-free survival (RFS), non-relapse mortality, and GVHD-free/Relapse-free survival were as follows: 66.9% (95% CI 58.4-74), 59.9%, and 18.7% and 53.7%. KPS ≤ 80 was predictive of worst OS (P = .04). Those recipients who received MUD transplants had better RFS (P = .01).

Conclusions: RIC allo-HSCT combined with ATG and PTCy is safe and a potentially curative strategy and it is associated with impressive GRFS in AML.
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http://dx.doi.org/10.1111/ejh.13321DOI Listing
November 2019

Impact of central nervous system involvement in AML on outcomes after allotransplant and utility of pretransplant cerebrospinal fluid assessment.

Eur J Haematol 2019 Nov 5;103(5):483-490. Epub 2019 Sep 5.

Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

Objective: The primary objective was to assess the effect of central nervous system involvement in acute myeloid leukemia (CNS-AML) on outcomes after allogeneic hematopoietic stem cell transplant (allo-HCT). The secondary objective was to assess the utility of pretransplant cerebrospinal fluid (CSF) assessment in AML.

Methods: We retrospectively analyzed survival outcomes in 338 adult AML patients (with and without CNS-AML) after allo-HCT. CNS involvement was defined as clinical, pathological, or radiological evidence of CNS involvement any time after diagnosis.

Results: The median follow-up in surviving patients was 23.7 months. Twenty-five patients (7.4%) had prior history of CNS disease, with normal CSF pretransplant. Three patients had CSF blasts detected for the first time at pretransplant evaluation (0.88%). The 2-year OS and RFS in groups with and without CNS involvement were not significantly different. Patients with CNS-AML had significantly higher 1-year cumulative incidence of relapse (29.7% vs 16.9%, P = .048). Age more than 65 years and absence of marrow remission at transplant were significant adverse factors for survival.

Conclusion: CNS-AML is not an independent risk factor for survival after allo-HCT, but can be associated with higher relapse rates. Pretransplant CSF assessment has low yield in detecting new CNS disease pretransplant in AML.
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http://dx.doi.org/10.1111/ejh.13314DOI Listing
November 2019

Epstein-Barr virus associated post-transplant lymphoproliferative disorder mimicking acute graft versus host disease.

Eur J Haematol 2019 Nov 27;103(5):519-522. Epub 2019 Aug 27.

Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.

We present a case series of 3 patients to highlight the fact that PTLD post-transplant can mimic GVHD, and should be part of the differential diagnosis for diarrhea post allo-HCT. Awareness of this presentation has important therapeutic implications, as increased immune suppression for the management of GVHD, can worsen clinical features of PTLD. Diagnostic imaging and tissue biopsies should be undertaken early in post-transplant patients presenting with diarrhea or hepatic abnormalities, especially with atypical presentations like fever, and EBV PCR monitoring can expedite clinical decision-making in such complicated scenarios while awaiting results of gut biopsies.
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http://dx.doi.org/10.1111/ejh.13309DOI Listing
November 2019

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