ALBERT

Description: Introduction Graft versus host disease (GVHD) remains the most frequent and serious complication following allogeneic hematopoietic stem cell transplantation (HSCT). There is marked variability in GVHD prophylaxis regimens but the most commonly used is methotrexate (MTX) in combination with cyclosporine (CSA). However MTX toxicity can mandate dose reductions resulting in an increased risk of acute GVHD (aGVHD). There is limited and conflicting data on the efficacy of mycophenolate (MMF) in comparison to MTX. Methods and patients We retrospectively reviewed 242 consecutive patients who received related donor myeloablative peripheral blood stem cell transplantation between 2002 and 2012 at the Princess Margaret Cancer Centre, Toronto Canada. We compared patients who received MMF/CSA (n=71) (institutional standard of care since 2009), to a historical control who received MTX/CSA (n=171). MTX was given IV as 15 mg/m2 on day +1, and 10 mg/m2 on days +3, +6, and +11 post HSCT with adjustments made for mucositis, renal and liver dysfunction and effusions. MMF was given as 45mg/kg/day in 3 divided doses orally from day 0 to +30 post HSCT. In both GVHD prophylaxis regimens the CSA strategy was the same (5 mg/kg/day IV q12h starting day -1 aiming for therapeutic trough levels between 200-400 mcg/L). Routine surveillance of CMV viremia was performed using pp65 antigenemia (〉1 positive cell) until 2011 and thereafter this was performed using PCR (〉200 copies). There were no differences in patient characteristics except for age and conditioning regimens due to period effect and institutional changes in practice. Results There was no difference between the MTX/CSA and MMF/CSA groups in 3-year overall survival (66.1% vs 56.9%, p=0.09), 3-year non-relapse mortality (19.0% vs 27.4%, p=0.13) and relapse (15.5% vs 16.0%, p=0.56). Patients in the MMF/CSA group had significantly faster neutrophil and platelet engraftments: medians of 13 vs 18 days and 10 vs 14 days respectively (p

Description: Background: Azathioprine (AZA) has been used as a steroid sparing agent in allogeneic BMT program at the Princess Margaret Cancer Centre, Toronto, Canada for last two decades especially for cGVHD treatment. A previous clinical trial (Sullivan, Blood 1998) compared prednisone (PRD) alone vs PRD plus AZA for the treatment of extensive chronic GVHD (cGVHD) suggesting that PRD alone showed a better survival than PRD+AZA. However, the NIH consensus criteria (NCC, 2005) for cGVHD and new statistic endpoint to evaluate efficacy of cGVHD, failure free survival (FFS), have been recently introduced and increasingly used. Therefore, we conducted retrospective study attempted to evaluate the efficacy of PRD+AZA regimen compared to PRD alone regimen with respect to failure free survival (FFS) as well as overall survival (OS), non-relapse mortality (NRM)and relapse incidence. In order to adjust for the risk factors which affect the choice of treatment between different treatment options, propensity score matching (PSM) analysis was adopted in the present study. Methods: The patients diagnosed with late onset acute GVHD was excluded. A total of 240 patients were included in the analysis, transplanted at the Princess Margret Cancer Center between 2009 and 2013, diagnosed with cGVHD by NCC, and treated with PRD+AZA (n=98) or PRD alone (n=142) as first line treatment. Failure free survival (FFS), OS, NRM and relapse were compared between the 2 groups. A case-control study was performed with well-balanced pairs of PRD+AZA vs PRD patients. For the PSM analysis, propensity score (PS) was calculated. Clinical variables included in PS calculation were global score (GS) by NCC, subtype of cGVHD (classical vs overlapping), age, gender, duration from HCT to cGVHD initial treatment, performance status (PS), progressive type onset (PTO) of cGVHD, thrombocytopenia (TP) and each organ involvement of cGVHD per skin, gastrointestinal tract, liver, lung and musculoskeletal system. A total of 74 case-control pairs were selected within 0.1 of a difference in propensity score. RESULTS: With a follow-up of 43. 6 months, the 2-year FFS, OS, NRM and relapse incidence was 24.7 %, 75.6 %, 16.6% and 7.7%, respectively. The median FFS was 7.9 months (95% CI, 6.1-9.6 months). PRD+AZA group showed a longer FFS duration compared to PRD group (13.2 vs 5.6 months, p

Description: Introduction Large granular lymphocytes (LGL) are a morphologically recognizable subpopulation of lymphocytes comprising an immunophenotypically heterogeneous population of activated CD3+ T cells and CD3- natural killer (NK) cells that mediate non-MHC-restricted cytotoxicity. Increased number of circulating LGL can be found as a response to viral infections, autoimmune disease or malignant neoplasms, as a result of chronic antigenic stimulation. Of interest, LGL lymphocytosis has been reported to occur following hematopoietic cell transplantation (HCT), with a variable incidence of up to 20%. This population display improved transplant outcomes with a lower incidence of non-relapse mortality and relapse (Kim, BMT, 2013; Nann-Rütti, BBMT, 2012). The aim of the present study is to determine the risk factors associated with the development of LGL lymphocytosis after allogeneic HCT. Methods A total of 826 patients who underwent an allogeneic HCT at Princess Margaret Cancer Centre, Toronto, Canada from 2000 to 2012 were retrospectively analyzed. LGL lymphocytosis was defined as the presence of at least two of the followings: 1) Sustained peripheral blood lymphocyte count ≥3.0 x 109/L observed in at least three consecutive determinations over a period of 2-3 months; 2) Predominance (≥30%) of LGL lymphocytes in the peripheral blood, as assessed by morphologic or immunophenotypic criteria; 3) T-cell receptor monoclonality assessed by PCR. The patient population was divided into discovery and replication sets using 2 different methods: stratified randomization and propensity score matching, using relevant baseline variables such as donor type, CMV serostatus, conditioning, T-cell depletion. Results No significant imbalances were found between the discovery and replication sets in terms of relevant baseline characteristics and clinical outcomes, for both the randomly divided patients and the propensity score matched groups. The overall incidence of LGL lymphocytosis was 14.5% at 3 years. The incidence of LGL lymphocytosis was similar across all subgroups of patients, both for the randomly divided groups and the propensity score matching (P-value not significant). A multivariable analysis of the risk factors for the development of LGL lymphocytosis was performed, including the following variables: grades 3-4 acute graft-versus-host-disease (GVHD), chronic GVHD, CMV viremia, CMV serostatus of the recipient, donor type, transplant year and T-cell depletion (TCD) for GVHD prophylaxis. In the stratified randomization analysis, the following risk factors were identified: 1) Discovery set: chronic GVHD (Hazard Ratio: 8.3, 95% CI: 3.1-22.6, P

Description: Several studies have suggested a beneficial effect of CMV seropositivity and or reactivation on relapse risk after allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies. Inability to replicate this finding in T cell depleted HCT is suggestive of a potential effect modification between TCD and CMV in this setting, but this has not been addressed in previously published studies. We have retrospectively analyzed transplant outcomes in 192 patients with myeloid malignancies who have undergone unrelated donor HCT at our center during January 2006 –November 2013. Among this 111 patients received in vivo TCD with low dose (30 mg) alemtuzumab and 81 patients received non-TCD transplants. Recipients were CMV seropositive in 57% of TCD transplants and 59% of non-TCD transplants. Analysis showed a significant effect modification (p=0.03 for interaction) between alemtuzumab and CMV serostatus on relapse risk, and stratified analysis based on recipient CMV status showed inferior outcomes with alemtuzumab in CMV seropositive recipients but not in CMV seronegative recipients. In CMV seropositive recipients alemtuzumab was an independent predictor of higher relapse (Hazard Ratio=13.95, p=0.008), inferior relapse free survival (HR=2.30, p=0.002), and inferior overall survival (HR= 2.04, p=0.008). There was no difference in NRM between CMV seropositive and CMV seronegative groups, or between TCD and non-TCD transplants. These findings suggest the presence of an effect modification by TCD on CMV's effect on relapse, resulting in inferior transplant outcomes with low dose Alemtuzumab in CMV seropositive recipients, but not in seronegative recipients. Figure 1. CIR, NRM, RFS, and OS showing differential effects of T cell depletion between CMV seropositive and seronegative recipients (A-B) Cumulative incidence of relapse, (C-D) Non-relapse mortality, (E-F) Relapse free survival, and (G-H) Over all survival. Figure 1. CIR, NRM, RFS, and OS showing differential effects of T cell depletion between CMV seropositive and seronegative recipients. / (A-B) Cumulative incidence of relapse, (C-D) Non-relapse mortality, (E-F) Relapse free survival, and (G-H) Over all survival. Disclosures Off Label Use: Alemtuzumab for GVHD prophylaxis.

Description: Background: Prolongedsystemic immunosuppression (SIS) post allogeneic hematopoietic cell transplantation (HCT) results in increased unnecessary complications. In our previous study of avascular necrosis (AVN; ASBMT 2015), one of common complications occurring after allogeneic HCT related to the use of prolonged immunosuppression including corticosteroids, we demonstrated a strong correlation between the duration of SIS and the risk of AVN. The probability of remaining on SIS was higher in the group developed AVN than those without episode of AVN (46.4% vs 11.7% at 4 years post-HCT). The question remains what are the risk factors related to prolonged SIS after allogeneic HCT. The present study attempted to evaluate potential risk factors for prolonged SIS. Methods: A retrospective review of 845 consecutive patients ≥18 years of age who underwent alloHCT at Princess Margaret Cancer Centre from 2002 to 2013 was conducted to determine the probability of SIS discontinuation considering death and relapse as competing risks. Univariate and multivariate analyses were conducted using cumulative incidence method considering competing risk to identify the risk factors for failure from SIS discontinuation. Results: Out of 845 patients, the probability of remaining on SIS, SIS discontinuation and death at 4 years is 19.6%, 30.5%, 49.9%, respectively. The median follow up duration among survivors was 3.5 years. Univariate analysis for successful SIS cessation revealed following risk factors: aGVHD grade 2-4 (p

Description: Introduction: Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms that are increasingly recognized as clinically significant pathogens in the allogenic hematopoietic cell transplanted (alloHCT) population. The incidence of NTM infection post alloHCT has increased from 0.49-1.0% in early studies to 2.8-8.7% in more recent investigations, possibly due to improvements in NTM detection, varying pre-transplant conditioning regimens and regional epidemiology of different NTM species. We investigated incidence and risk factors of NTM infection after alloHCT. Methods & Patients: Medical records for 1097 consecutive patients who underwent alloHCT at Princess Margaret Cancer Centre from 2000 to 2013 were reviewed to determine the frequency, risk factors and outcomes associated with NTM infections. Clinically significant NTM infection was differentiated from colonization according to the American Thoracic Society guidelines, and was classified as pulmonary, non-pulmonary, or disseminated. Acute and chronic graft versus host disease (aGVHD and cGVHD) were diagnosed and graded using established and NIH consensus criteria respectively. The cumulative incidence of NTM was calculated considering competing risks of death. Multivariate analysis comprised Cox proportional hazards regression, modeling NTM risk. Statistical analyses were performed using EZR software (Saitama, Japan). Results: Of 1097 patients, NTM were isolated in 45 (4.1%) and judged clinically significant in 30 (2.7%). The incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9-4.0%). The median (range) time to diagnosis was 343 (19-1967) days, and in 83% of patients, was diagnosed within 2 years of alloHCT. Of the 30 clinically significant NTM infections, 28 (93.3%) were pulmonary and 2 (6.7%) were disseminated. With respect to the latter group, one patient had NTM isolated from blood, while the second case was presumed disseminated based on characteristic skin findings, but with no confirmed microbiologic diagnosis. The most common species/groups isolated were Mycobacterium avium complex (n=11, 36.7%), M. xenopi (n=5, 16.7%), and M. fortuitum (n=5, 16.7%). 22/30 patients (73.3%) were on systemic immunosuppression at the time of diagnosis, and 95.7% had concurrent infections (30.4% pulmonary, 17.3% extra-pulmonary, and 47.8% both), with fungal infections occurring most frequently (53.3%). Significant risk factors (HR 95% CI) for NTM included aGVHD grades 2-4 (3.25 [1.33-7.96] p=0.036), cGVHD (3.20 [1.06-9.68] p=0.010), age (1.05 [1.02-1.07], p

Description: Abstract 3056 Background: The pathogenesis of GVHD is not fully understood. Alloreactive T-lymphocytes are believed to be key mediators of GVHD. However, it is not clear if the pathobiology of GHVD is similar in each target organ GVHD. We aimed to identify predictive single nucleotide polymorphisms (SNP) markers associated with the risk of acute or chronic graft versus host disease (GVHD) as well as organ specific GVHD in 394 transplant recipients and donors. Methods: A total of 259 SNPs were genotyped in 53 genes, and evaluated for the risk of acute/chronic GVHD and organ specific GVHD. Predictive models were generated using both clinical factors and genetic SNP markers confirmed by multivariate analyses. Patients were stratified by quartile (25%) according to their risk score, and the risk of overall and organ specific GVHD were compared among the 3 risk groups (low, intermediate and high risk). C-statistic analysis was also performed to compare the stratification power of the predictive model generated using clinical and genetic factors with a model obtained using only clinical factors. Results: Several SNP markers in the cytokine-, apoptosis-, TGF-¥â or PDGF-mediated pathways were identified as predictive markers of acute/chronic GVHD. The risk of acute GVHD was associated with clinical factors such as HLA disparity and patient age. In addition, recipient FAS genotype (rs2234978), EDN1 genotype (rs4714384), and TGFB genotype (rs1800469), and donor TNFRII genotype (rs3397) were also strong predictive markers for acute GVHD. Significant predictive risk factors forchronic GVHD were the source of stem cells, a previous episode of acute GVHD and the donor IL1R1 genotype (rs3917225). Each organ specific GVHD shared common biologic pathways such as cytokine, TGF-¥â or PDGF-mediated pathways. However, different SNP markers were identified as predictive for individual organ-specific GVHD. Multivariate analyses identified several SNP markers may predict the risk of organ specific acute GVHD in combination with clinical factors. For skin acute GVHD, recipient PDGFD (rs10895534), donor NOS2A (rs3730017), TNFRII (rs3397) and TGFB1 (rs1800469) genotypes were predictive together with clinical factors such as HLA disparity. Donor's genotype for TNFRII (rs3397) was predictive not only for overall acute GVHD but also for skin acute GVHD. No clinical factors were identified for the risk of liver or gut acute GVHD, but several SNP markers were found including recipient PDGFRB (rs2302273), IFNGR1 (rs2234711) and donor PTGS1 (rs10306114), NOS1 (rs9658254), IL1R1 (rs2192752) genotypes for liver acute GVHD and recipient IL4 (rs2243248), donor PDGFD (rs1053861), TGFBR1 (rs420549), IL12A (rs2243115) genotypes for gut acute GVHD. In summary, there are no overlapping SNP markers for the risk prediction of organ specific acute GVHD. For organ specific chronic GVHD, 2 clinical risk factors were predictive including source of stem cells and a preceding history of acute GVHD. In addition, several SNP markers were also identified: recipient PDGFC (rs1425486), donor NFKB1 (rs1805034) and NOS2A (rs3730017) for skin chronic GVHD; recipient IL10RB (rs8178561) and PDGFRB (rs22229562), and donor TGFBR1 (rs868) for eye chronic GVHD; recipient IL12RB1 (rs3746190) and donor FCGR2A (rs1801274) for oral chronic GVHD; and donor IL4R (rs2057768), FAS (rs2234767) and TGFB1 (rs1800469) for lung chronic GVHD. Again, In no overlapping SNP markers were observed for organ-specific chronic GVHD risk. Although this predictive model could not stratify patients according to their risk of overall chronic GVHD (p=0.0763), the predictive models per each organ specific chronic GVHD enabled to stratify the patients according to their risks of each organ specific GVHD (p

Description: Introduction: Varicella zoster (VZV) infection is a common complication post allogeneic hematopoietic stem cell transplantation (HCT) associated with significant morbidity, such as post herpetic neuralgia and secondary bacterial infection. Strategies to diminish the incidence of VZV infection include the use of prophylactic antivirals with some controversy. Our previous studies have explored risk factors associated with the incidence of VZV infection in 192 patients (Kim, Transplant Infectious Diseases, 2007). We attempted to determine the incidence of VZV infection and to explore risk factors leading to the development of VZV infection in an extended cohort of 1,045 patients receiving alloHCT. Methods: A retrospective single center study was conducted at Princess Margaret Cancer Centre, Toronto, Canada. Medical record review was performed for 1,045 consecutive patients who had undergone an alloHCT from 2001 to 2013. VZV infection was determined by clinical features and/or microbiologic determination. The incidence of VZV infection was calculated using cumulative incidence method considering death and relapse as competing risks. Univariate and multivariate analyses were conducted using EZR to identify the risk factors for VZV infection. Results: Out of 1,045 patients, 142 cases were identified with VZV infection (13.6%) with 14.4% of VZV incidence at 5 years (95% CI, 12.3-16.8%). The median days to the diagnosis of VZV post allogeneic transplantation was 231 days (range, 27-1488 days). 86.6% of patients were diagnosed as having VZV within 2 years post transplantation. 52.1% of those who developed VZV developed post-herpetic neuralgia, while 14.8% developed disseminated VZV. A univariate analysis was conducted including the following risk factors: aGVHD grade 2-4, aGVHD grade 3-4, occurrence of cGVHD, cGVHD severity by NIH consensus criteria, diagnosis (lymphoid v. others), T-cell depletion for GVHD prophylaxis, donor (related v. unrelated), HLA (matched v. mismatched) and donor type (matched related v. matched unrelated v. mismatched). Risk factors that were significant on univariate analysis were cGVHD occurrence by NIH criteria (p

Description: Introduction: It is extremely significant issue to predict hematopoietic stem cell transplant (HSCT) outcomes using a biomarker. In this study, we attempted to evaluate the impact of post-transplant serum albumin on outcomes in patients with acute lymphoblastic leukemia (ALL). Methods: 123 patients with ALL receiving HSCTs between 1999 and 2012 at our center were evaluated for post-transplant serum albumin levels and their correlation with transplant's outcome. The level of serum albumin was retrospectively retrieved in certain time point ± 3 days for following periods: 1 month pre HSCT and then weekly after transplantation for first 3 months. 100 patients had available serum albumin levels. The ROC analyses were used to determine the most statistically significant cutoff level of serum albumin level correlating with NRM at 1 year. The ROC analysis suggested the level of 32 g/l at 4 weeks post HSCT as the best cutoff level for further analysis. Thus patients were stratified into low versus high albumin level group according to that cutoff level. Results: Median age for all patients is 37 (range 17-61), 35% were female and related donors were 57%. Matched donors were 83%. 71% were in 1st complete remission. 37% were Philadelphia chromosome positive. GVHD prophylaxis was CSA/MTX 60%, CSA/MMF 22%. Conditioning regimen was myeloablative in 95%. 61% received peripheral blood stem cells. With a median follow-up among survivors of 60 months (range 21-100), 61% patients showed albumin level ³ 32g/l at day 30 while 39% showed dropped albumin level