Publications by authors named "Dennis Dong Hwan Kim"

68 Publications

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

Eur J Haematol 2021 Jan 9. Epub 2021 Jan 9.

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
January 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

Allogeneic transplant can abrogate the risk of relapse in the patients of first remission acute myeloid leukemia with detectable measurable residual disease by next-generation sequencing.

Bone Marrow Transplant 2020 Dec 5. Epub 2020 Dec 5.

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

In patients with acute myeloid leukemia (AML) consolidation treatment options are between allogeneic hematopoietic stem cell transplantation (HCT) and chemotherapy, based on disease risk at the time of initial presentation and age. Measurable residual disease (MRD) following induction chemotherapy could be incorporated as a useful parameter for treatment decisions. The present study evaluated treatment outcomes according to the next-generation sequencing (NGS)-based MRD status and the type of consolidation therapy in patients with normal karyotype (NK)-AML. By sequencing 278 paired samples collected at diagnosis and first remission (CR1), we identified 361 mutations in 124 patients at diagnosis and tracked these at CR1. After excluding mutations associated with age-related clonal hematopoiesis, 82 mutations in 50 of the 124 patients (40.3%) were detected at CR1. Survival benefit was observed in favor of allogeneic HCT over chemotherapy consolidation in the MRD subgroup with respect to overall survival (HR 0.294, p = 0.003), relapse-free survival (HR 0.376, p = 0.015) and cumulative incidence of relapse (HR 0.279, p = 0.004) in multivariate analysis, but not in the MRD subgroup. In summary, these data support allogeneic HCT in NK-AML patients with detectable MRD by NGS in CR1. Randomized clinical trials will be required to confirm this observation.
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http://dx.doi.org/10.1038/s41409-020-01165-xDOI Listing
December 2020

RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia.

Sci Rep 2020 11 18;10(1):20119. Epub 2020 Nov 18.

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

DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). Here in this study, we evaluated the effectiveness of using DNA and RNA sequencing in MRD detection and in tracking clonal dynamics in CBF-AML. Using RNA-seq, we were able to quantify expression levels of RUNX1-RUNX1T1 and CBFB-MYH11 at diagnosis and their levels of reduction during remission (P < 6.3e-05 and P < 2.2e-13). The level of reduction of RUNX1-RUNX1T1 as measured by RNA-seq and qPCR were highly correlated (R = 0.74, P < 5.4e-05). A decision tree analysis, based on 3-log reduction of RUNX1-RUNX1T1 and cKIT-D816 at diagnosis, stratified RUNX1-RUNX1T1 AML patients into three subgroups. These three subgroups had 2-year overall survival rates at 87%, 74%, and 33% (P < 0.08) and 2-year relapse incidence rates at 13%, 42%, and 67% (P < 0.05). On the other hand, although low residual allelic burden was common, it was not associated with long-term outcome, indicating that mutation clearance alone cannot be interpreted as MRD-negative. Overall, our study demonstrates that the clinical utility of RNA sequencing as a potential tool for MRD monitoring in fusion gene-driven AML such as RUNX1-RUNX1T1 AML.
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http://dx.doi.org/10.1038/s41598-020-76933-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674449PMC
November 2020

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

Effect of donor age and kinship on outcomes in haplo-identical stem cell transplantation may be modulated by GVHD prophylaxis strategies.

Bone Marrow Transplant 2020 Aug 14. Epub 2020 Aug 14.

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

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http://dx.doi.org/10.1038/s41409-020-01030-xDOI Listing
August 2020

High incidence but low mortality of EBV-reactivation and PTLD after alloHCT using ATG and PTCy for GVHD prophylaxis.

Leuk Lymphoma 2020 12 25;61(13):3198-3208. Epub 2020 Jul 25.

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

We explore risk factors and impacts of post-transplant EBV-Reactivation (EBV-R) and PTLD in 270 patients that underwent RIC alloHCT using ATG-PTCy and cyclosporine for GVHD prophylaxis. Twenty-five (12%) patients had probable ( = 7) or proven ( = 18) PTLD. Patients were managed with reduction of immunosuppression and 22 with weekly rituximab (375 mg/m IV). ORR was 84%; 8 (32%) recipients died, and one-year OS and NRM of patients with PTLD was 59.7% and 37%, respectively. One hundred seventy-two (63.7%) recipients had EBV-R. One-year OS and RFS of patients with EBV-R were 68.2% and 60.6%, and of EBV-Negative patients were 62.1% and 50.1%, respectively. High incidence but low mortality of EBV-R and PTLD was documented. EBV-R induced a protective effect on RFS in multivariable analysis (HR 0.91,  = .011). Therefore, EBV-R may have a protective effect on RFS in this setting. Further research is necessary to evaluate the interplay of EBV-R, immune reconstitution, and post-transplant outcomes.
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http://dx.doi.org/10.1080/10428194.2020.1797010DOI Listing
December 2020

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

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

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

Are we ready to use precision medicine in chronic myeloid leukemia practice?

Haematologica 2019 12;104(12):2327-2329

Leukemia Program, Department of Medical Oncology and Hematology, Princess Margraret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada

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http://dx.doi.org/10.3324/haematol.2019.231753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959187PMC
December 2019

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

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

Evidence that 6q25.1 variant rs6931104 confers susceptibility to chronic myeloid leukemia through RMND1 regulation.

PLoS One 2019 25;14(6):e0218968. Epub 2019 Jun 25.

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

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Our previous study reported novel loci as genetic markers associated with increased susceptibility to CML. The present study conducted an expression quantitative trait loci (eQTL) analysis to confirm that the single nucleotide polymorphisms (SNPs) at these loci affect the expression of candidate CML-susceptible genes. We identified that three SNPs (rs963193, rs6931104, and rs9371517) were related to the gene expression pattern of RMND1 (Required For Meiotic Nuclear Division 1 Homolog) in both granulocytes and mononuclear cells from 83 healthy donors. Furthermore, reduced expression of RMND1 expression was noted in CML patients compared with that in healthy individuals. We used the eQTL browsing tool to assess the regulatory information on the three associated significant SNPs, out of which rs6931104 showed strong evidence of regulatory effects. Chromatin immunoprecipitation (ChIP) assays demonstrated that A alleles of rs6931104 could significantly change the binding affinity of transcription factor (TF) RFX3 compared to the G alleles. Then, we performed in vitro experiments on BCR-ABL1-positive (BCR-ABL1+) cell lines. We found that expression of the CML-susceptible gene RMND1 is affected by the binding affinity of TF RFX3, suggesting that RFX3 plays a role in RMND1 expression. Our findings suggest potential target genes for associations of genetic susceptibility risk loci and provide further insights into the pathogenesis and mechanism of CML.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218968PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592567PMC
February 2020

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia.

Leukemia 2019 08 17;33(8):1835-1850. Epub 2019 Jun 17.

School of Medicine, University of Adelaide, Adelaide, Australia.

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.
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http://dx.doi.org/10.1038/s41375-019-0512-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893870PMC
August 2019

Remission clone in acute myeloid leukemia shows growth advantage after chemotherapy but is distinct from leukemic clone.

Exp Hematol 2019 07 12;75:26-30. Epub 2019 Jun 12.

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

In a previously published case study of acute myeloid leukemia, we tracked the dynamics of somatic mutations over 9 years. Interestingly, we observed a group of mutations that expanded during remission, which we named the "remission clone." To determine the nature of the remission clones, we performed flow cytometry-based cell sorting followed by ultradeep sequencing. The remission clone repeatedly expanded after chemotherapeutic cycles and was suppressed during relapse in the myeloid lineage (multipotent hematopoietic stem, progenitor, and myeloid cells). On the other hand, the remission clone was consistently observed in lymphoid lineages (B and T cells) regardless of the disease state. When transfected into the HEK-293 cell line, the NR2C2(A93V) mutant exhibited a growth advantage (all p values < 0.05). The results indicate that the remission clone seems to be another form of clonal hematopoiesis, but without a clear association with leukemia. As the remission clone is present in both myeloid and lymphoid lineages, it likely originates from ancestral hematopoietic cell lineages. More importantly, the remission clone is distinct from the leukemic clone; therefore, mutations expanded during remission require special interpretation when performing next-generation sequencing-based measurable residual disease assessment.
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http://dx.doi.org/10.1016/j.exphem.2019.06.001DOI Listing
July 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

Low rates of acute and chronic GVHD with ATG and PTCy in matched and mismatched unrelated donor peripheral blood stem cell transplants.

Eur J Haematol 2019 Jun 29;102(6):486-493. Epub 2019 Apr 29.

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

Introduction: We evaluated the combination of ATG and PTCy for GVHD prophylaxis in matched and mismatched unrelated PBSCTs for high-risk hematological malignancies.

Methods: We treated 102 patients with reduced intensity conditioning (RIC) with fludarabine, busulfan, and TBI 200 cGy. GVHD prophylaxis included rabbit ATG (thymoglobulin at total dose of 4.5 mg/kg divided over days -3 to -1), PTCy (50 mg/kg/day on day +3 and on day +4), and cyclosporine. Clinical and outcome data were collected retrospectively.

Results: Among 102 patients, 76 patients received 10/10 MUD transplants and 26 patients received 9/10 mismatched transplants. The median age was 59 years. At a median follow-up of 15 months (range 0.6 to -33 months), the 1-year OS in MUD and MMUD cohort was 75% and 50%, respectively (P = 0.027). The corresponding one-year PFS was 67% and 35%, respectively (P = 0.0024). The incidence of grade 3-4 acute GVHD was 11.8% in MUD and 3.8% in MMUD group, and that of NIH stage moderate/severe chronic GVHD in the 2 groups was 10.5% and 7.6%, respectively. Cytomegalovirus (CMV) reactivation was seen in 49% patients. The cumulative incidence of relapse was 21.1% in the MUD group and 42.3% in the MMUD group.

Conclusion: Our experience shows that PTCy and ATG can be combined for GVHD prophylaxis in matched unrelated donor PBSCTs with low rates of Gr3-4 acute GVHD and chronic GVHD, and acceptable relapse rates.
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http://dx.doi.org/10.1111/ejh.13230DOI Listing
June 2019

HMGCLL1 is a predictive biomarker for deep molecular response to imatinib therapy in chronic myeloid leukemia.

Leukemia 2019 06 16;33(6):1439-1450. Epub 2018 Dec 16.

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

Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1 variant in a discovery set of CML patients (n = 201) and successfully replicated it in a validation set (n = 270). We also investigated the functional relevance of HMGCLL1 blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1 isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1 kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1 was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1 gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.
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http://dx.doi.org/10.1038/s41375-018-0321-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756062PMC
June 2019

Next-generation sequencing-based minimal residual disease monitoring in patients receiving allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia or myelodysplastic syndrome.

Curr Opin Hematol 2018 11;25(6):425-432

Allogeneic Blood and Marrow Transplant Program, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Purpose Of Review: The monitoring of minimal residual disease (MRD) has important clinical implications in both the pre and postallogeneic stem cell transplant (SCT) setting in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Next-generation sequencing (NGS) is a rapidly improving technology whose application to the monitoring of MRD is an active area of research. We aim to describe existing methods of MRD in AML and MDS, with a focus on the utility of NGS in patients undergoing SCT.

Recent Findings: Flow cytometry and quantitative PCR have been recommended by the European Leukemia Net as the preferred methods of MRD in AML and MDS, but these methods have limitations in cases without a disease-defining phenotype and genotype. Clinical trials are currently ongoing to assess the use of NGS in the setting of SCT for MDS and AML. Few studies have so far assessed the optimal method of MRD monitoring in the posttransplant setting.

Summary: The optimal method for the monitoring of MRD in AML and MDS both pre and post transplant may require more than one technology. NGS holds great promise for the monitoring of MRD, with prospective trials currently ongoing to evaluate its efficacy in this regard.
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http://dx.doi.org/10.1097/MOH.0000000000000464DOI Listing
November 2018

Canadian chronic myeloid leukemia outcomes post-transplant in the tyrosine kinase inhibitor era.

Leuk Res 2018 10 5;73:67-75. Epub 2018 Sep 5.

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

The majority of patients with TKI failure respond to HCT. However, the relapse risk remains high. This study has evaluated transplant outcomes in 223 CML patients with TKI failure due to resistance (n = 132) or intolerance (n = 29), as well as those that were TKI naïve/responding with advanced disease (n = 35) or with chronic phase (CP, n = 27). We studied outcomes according to post-transplant BCR-ABL transcript level within 3 months. With respect to transplant outcomes according to the post-transplant BCR/ABLtranscript level within 3 months, the group failing to achieve a 1.3 log reduction (n = 14, 12.4%) showed the highest relapse rate of 78.6% at 5 years, compared to 26.2% and 24.1% in the groups achieving 1.3-4.0 log reduction (n = 45, 39.8%), and ≥4.1 log reduction (n = 54, 47.8%) respectively (p < 0.001). Multivariate analysis confirmed that the group failing to achieve a 1.3 log reduction had a 2.3-fold higher risk of death and 6.6 times higher risk of relapse. Poor overall survival after HCT was associated with advanced disease at diagnosis, but not disease status prior to HCT. Of 61 patients who relapsed after HCT, 47 were treated with post-transplant TKI therapy; those receiving TKI after loss of MR2 or MMR showed higher rates of response and survival compared to those receiving TKI after hematologic relapse (p < 0.001). QPCR log reduction level within 3 months post transplantation is prognostic in this population.
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http://dx.doi.org/10.1016/j.leukres.2018.08.021DOI Listing
October 2018

Next-generation sequencing-based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse.

Blood 2018 10 14;132(15):1604-1613. Epub 2018 Aug 14.

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

Next-generation sequencing (NGS) has been applied to define clinically relevant somatic mutations and classify subtypes in acute myeloid leukemia (AML). Persistent allelic burden after chemotherapy is associated with higher relapse incidence, but presence of allelic burden in AML patients after receiving allogeneic hematopoietic cell transplantation (HCT) has not been examined longitudinally. As such, we aimed to assess the feasibility of NGS in monitoring AML patients receiving HCT. Using a targeted gene panel, we performed NGS in 104 AML patients receiving HCT using samples collected at diagnosis, pre-HCT, and post-HCT at day 21 (post-HCT). NGS detected 256 mutations in 90 of 104 patients at diagnosis, which showed stepwise clearances after chemotherapy and HCT. In a subset of patients, mutations were still detectable pre-HCT and post-HCT. Most post-HCT mutations originate from mutations initially detected at diagnosis. Post-HCT allelic burdens in relapsed patients were higher than in nonrelapsed patients. Post-HCT mutations in relapsed patients all expanded at relapse. Assessment of variant allele frequency (VAF) revealed that overall VAF post-HCT (VAF-post-HCT) is associated with an increased risk of relapse (56.2% vs 16.0% at 3 years; < .001) and worse overall survival (OS; 36.5% vs 67.0% at 3 years; = .006). Multivariate analyses confirmed that VAF-post-HCT is an adverse prognostic factor for OS (hazard ratio [HR], 3.07; = .003) and relapse incidence (HR, 4.75; < .001), independent of the revised European LeukemiaNet risk groups. Overall, current study demonstrates that NGS-based posttransplant monitoring in AML patients is feasible and can distinguish high-risk patients for relapse.
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http://dx.doi.org/10.1182/blood-2018-04-848028DOI Listing
October 2018

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