ALBERT

Description: Post-transplant lymphoproliferative disorders (PTLDs) are classified as early PTLDs (E-PTLD), polymorphic PTLDs (P-PTLD), monomorphic PTLDs (M-PTLD) and classical Hodgkin's Lymphoma PTLD (HL). These entities are felt to represent a disease continuum, with a precursor-product relationship, though they are morphologically and clinically distinct. However, this process remains poorly understood, and limited evidence exists to support this hypothesis. We report a series of nine cases extracted from a PTLD database, including both pediatric and adult solid organ transplant recipients, with recurrent disease episodes that evince an apparent evolution in their morphologic categorization between episodes. All patients identified were high risk for PTLD, with multiple identifiable predisposing factors. Presentations varied from isolated lymphadenopathy, to gastrointestinal involvement to pulmonary involvement. Four of the patients were deceased at the time of acquisition, though only one directly from PTLD. Eight of the nine identified patients developed E or P-PTLD lesions that preceded a subsequent M-PTLD or HL lesion at a similar tissue site. Two of the cases had metachronous P and M-PTLD lesions. The six M-PTLD subtypes were variable, including DLBCL, Burkitt, T-cell, and extramedullary plasmacytoma, in addition to the three cases of classical Hodgkin's lymphoma. These cases suggest that E and P-PTLD may act as common precursor lesions to the development of both the M-PTLD variants and HL type lesions, and that the PTLD classification schema represents different stages of a common underlying pathology. Disclosures Owen: Lundbeck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria.

Description: Introduction The host immune status is central to both the pathogenesis and treatment of Post-Transplant Lymphoproliferative Disorders. (PTLD) The most commonly used prognostic model for PTLD, the International Prognostic Index (IPI), currently does not account for the effect of immune status on patient outcomes. We hypothesize that CD3 positive T-cell infiltrate density in the tumor microenvironment, thought to be a surrogate of the potency of the host versus tumor immune response, may be prognostic of overall survival in PTLD. Methods A database consisting of 131 biopsy confirmed PTLD cases occurring in pediatric and adult solid organ transplant recipients after the year 2000 in Alberta, Canada was analyzed for clinical prognostic variables and overall survival. CD3 infiltrate was determined by a blinded pathologist (JZ) using a standardized integer scoring system (0 - 3) to quantify CD3-positive cells in archived, formalin-fixed paraffin embedded tissue stained by immunohistochemistry. Tissue was available and assessed on a total of 72 patients. Survival analysis was done by Cox regression, with between group differences tested by a Pearson's chi-square test, with p 〈 0.05 being taken as significant. Results Median age at diagnosis was 40.2 years. Histology subtypes included early (n = 7), polymorphic (n = 17), monomorphic, (n = 100) Hodgkin, (n = 8) and unavailable. (n = 2) Immune suppression regimens at diagnosis included tacrolimus + mycophenolate (n = 29), tacrolimus + azathioprine (n = 11), cyclosporine + mycophenolate (n = 14), cyclosporine + azathioprine (n = 4), single agent tacrolimus (n = 11), single agent cyclosporine (n = 2), and other immunosuppressive regimens. (n = 4) A denser CD3 T-cell infiltrate, defined as a CD3 score of 2-3, had a statistically significant protective effect by univariate Cox regression with respect to overall survival. (HR 0.352, p = 0.008) A CD3 score of 2-3 was negatively associated with a monomorphic histology (p 〈 0.001), but was not statistically associated with lymphocyte count, early PTLD, EBV status or bone marrow involvement. In the diffuse large B-cell type PTLD subgroup (n = 61) the association of a dense CD3 T-cell infiltrate with an improved OS was preserved. (HR 0.276, p = 0.041) Clinical factors identified as significant by univariate Cox regression with respect to overall survival included age 〈 18 (HR = 0.380, p = 0.010), monomorphic histology (HR = 2.287, p = 0.02), IPI 3-5 (HR = 3.697, p 〈 0.001), BM involvement (HR 2.437, p = 0.008), and lymphocyte count 〈 1.0. (HR 2.449, p = 0.001) Clinical factors deemed to not be significant with respect to overall survival by univariate Cox regression included CD20 (p = 0.730), thoracic transplant organ (p = 0.314), PTLD onset within 1 year of transplant (p = 0.763), allograft involvement (p = 0.253), albumin of 〈 30 (p = 0.062) and tumor EBV status. (p = 0.278) Multivariate Cox regression with respect to overall survival, including monomorphic histology, IPI 3-5, lymphocyte count 〈 1.0 and CD3 score of 2-3 again showed a statistically significant protective effect of a higher CD3 score. (HR 0.307, p = 0.022) No other clinical variables reached significance in the multivariate analysis. Conclusions A dense CD3 T-cell infiltrate in the tumor microenvironment at diagnosis is protective with regards to overall survival in PTLD by both univariate and multivariate Cox regression, versus traditional clinical prognostic markers. This is reflective of the prognostic importance of the host immune response, which can be altered by changes in exogenous immunosuppression. In the future, validated histologic measures of immune status such as the CD3 score may be integrated into existing models, such as the IPI, to provide additional prognostic power in PTLD. Table 1 Baseline Patient Characteristics - A database with 131 pediatric and adult solid organ transplant recipients with PTLD were analyzed for clinical prognostic factors and available formalin fixed paraffin embedded tissue stained for CD3 by immunohistochemistry. Table 1. Baseline Patient Characteristics - A database with 131 pediatric and adult solid organ transplant recipients with PTLD were analyzed for clinical prognostic factors and available formalin fixed paraffin embedded tissue stained for CD3 by immunohistochemistry. Table 2 CD3 Score by Univariate Analysis - A univariate Cox regression was carried out for a CD3 score of 2-3 versus 0-1 for all analyzed samples. (n = 72) * denotes the reference variable. Table 2. CD3 Score by Univariate Analysis - A univariate Cox regression was carried out for a CD3 score of 2-3 versus 0-1 for all analyzed samples. (n = 72) * denotes the reference variable. Table 3 CD3 score by Multivariate Analysis versus Clinical Factors - A multivariate Cox regression was performed for a CD3 score of 2-3, versus selected clinical factors identified by univariate Cox regression. Table 3. CD3 score by Multivariate Analysis versus Clinical Factors - A multivariate Cox regression was performed for a CD3 score of 2-3, versus selected clinical factors identified by univariate Cox regression. Disclosures Owen: Janssen: Honoraria; Gilead: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Lundbeck: Honoraria, Research Funding; Novartis: Honoraria; Roche: Honoraria, Research Funding.

Description: Introduction Acute myeloid leukemia (AML) in older adults is a challenging clinical problem with a poor prognosis. Hypomethylating agents, such as azacitidine, improve survival in this population. (Oran B, Haematologica 2012) These treatments can be challenging to deliver, particularly in patients far from tertiary care centres. We examined whether residence outside of a major metropolitan area impacted referral patterns, treatments, and outcomes in a population-based cohort of AML patients over age 60 in British Columbia (BC), Canada. Methods Patients with ICD-10 diagnoses of AML were identified from the population based BC Cancer registry and BC Cancer pharmacy database. Diagnoses between 2010 and 2016 were included. Exclusion criteria included diagnosis age less than 60 years, any treatment outside BC, or APL. The diagnosis of AML was verified by chart review. Azacitidine was available at our institution in 2010, and is used primarily for patients with bone marrow blast counts below 30%. Patients were defined as having a hematologist/oncologist assessment if a provider with these credentials was listed in notes or pathology reports. Patients were defined as having received a treatment if it was dispensed at least once, with a date after AML diagnosis. Patients were defined as urban if they had a mailing address in a center of 〉/= 100,000 people, per the Statistics Canada definition, and rural if they had a mailing address elsewhere. Urban residences included greater Vancouver, Victoria and Kelowna, which comprise 71.5% of the population. (Statistics Canada, 2016 census) Between group differences were assessed by 2-tailed t-test or chi-square tests. Overall survival (OS) was assessed by Kaplan-Meier, with a log-rank test, and Cox regression. A p 〈 0.05 was significant. Results A total of 879 patients over age 60 with AML, excluding APL, were identified. Of these, 525 (60%) resided in urban areas vs 354 (40%) residing in rural areas. These groups were similar for median age at diagnosis (urban 75.9 years, rural 74.3 years, p = 0.067), adverse cytogenetic profile (urban 56%, rural 44%, p = 0.356), NPM1 positivity (urban 69%, rural 31%, p = 0.101) and FLT3 positivity (urban 76%, rural 24%, p = 0.052). Rural residents were less likely to have a documented hematologist/oncologist assessment (urban 84%, rural 65%, p 〈 0.001). Few patients overall received induction chemotherapy (151, 17%), with no difference between rural and urban residency (p = 0.524). Similarly, few patients underwent hematopoietic stem cell transplantation (38, 4%), with no difference with place of residence (p = 1.000). Median OS for patients treated with induction chemotherapy was 11.0 months (95% CI 9.0 - 13.1 mo). Median OS for patients treated with subcutaneous (SC) azacitidine was 7.1 months (95% CI 4.8 - 9.5 mo) vs 4.7 months (95% CI 3.3 - 6.1 mo) with SC cytarabine. With best supportive care, the median OS was 1.7 months (95% CI 1.5 - 1.9 mo). Median follow-up was 43.7 months (95% CI 39.2 - 48.2 mo), with 706 (97%) of patients deceased at last follow-up. Amongst the 728 patients who did not receive induction chemotherapy, 82 (11%) received SC cytarabine and 127 (17%) received SC azacitidine. Place of residence did not impact whether patients received SC cytarabine (urban 10%, rural 13%, p = 0.285). Rural residents were, however, less likely to receive SC azacitidine (urban 21%, rural 12%, p = 0.002). In patients not undergoing induction, rural residents had a worse OS by Kaplan-Meier analysis (p = 0.021), with a hazard ratio of 1.2 (95% CI 1.026 - 1.387, p = 0.022) on univariate Cox regression. Conclusions Older adults with a diagnosis of AML who reside in rural areas of BC are less likely to have a documented hematologist/oncologist assessment, and are less likely to receive SC azacitidine. This group also has a worsened OS, though the effect size is modest. There was no difference in rates of treatment with potentially curative regimens, although this approach applied to a minority of patients. We hypothesize that this difference may be partially due to the travel burdens placed on rural patients who receive SC azacitidine, which must be administered in a healthcare facility, unlike SC cytarabine. Less access to supportive care in rural areas is also likely a contributing factor. Policymakers should direct additional resources for rural oncologic healthcare delivery, and the importance of low burden drug formulations is AML should be emphasized. Disclosures No relevant conflicts of interest to declare.