Musa Alzahrani

Outcome prediction by extranodal involvement, IPI, R-IPI, and NCCN-IPI in the PET/CT and rituximab era: A Danish–Canadian study of 443 patients with diffuse-large B-cell lymphoma

18F‐fluorodeoxyglucose PET/CT (PET/CT) is the current state‐of‐the‐art in the staging of diffuse large B‐cell lymphoma (DLBCL) and has a high sensitivity for extranodal involvement. Therefore, reassessment of extranodal involvement and the current prognostic indices in the PET/CT era is warranted. We screened patients with newly diagnosed DLBCL seen at the academic centers of Aalborg, Copenhagen, and British Columbia for eligibility. Patients that had been staged with PET/CT and treated with R‐CHOP(‐like) 1st line treatment were retrospectively included. In total 443 patients met the inclusion criteria. With a median follow‐up of 2.4 years, the 3‐year overall (OS) and progression‐free survival (PFS) were 73% and 69%, respectively. The Ann Arbor classification had no prognostic impact in itself with the exception of stage IV disease (HR 2.14 for PFS, P<0.01). Extranodal involvement was associated with a worse outcome in general, and in particular for patients with involvement of >2 extranodal sites, including HR 7.81 (P < 0.001) for PFS for >3 sites. Bone/bone marrow involvement was the most commonly involved extranodal site identified by PET/CT (29%) and was associated with an inferior PFS and OS. The IPI, R‐IPI, and NCCN‐IPI were predictive of PFS and OS, and the two latter could identify a very good prognostic subgroup with 3‐year PFS and OS of 100%. PET/CT‐ascertained extranodal involvement in DLBCL is common and involvement of >2 extranodal sites is associated with a dismal outcome. The IPI, R‐IPI, and NCCN‐IPI predict outcome with high accuracy. Am. J. Hematol. 90:1041–1046, 2015.

The value of routine bone marrow biopsy in patients with diffuse large B-cell lymphoma staged with PET/CT: a Danish-Canadian study

BACKGROUND The added diagnostic and prognostic value of routine bone marrow biopsy (BMB) in patients with diffuse large B-cell lymphoma (DLBCL) undergoing positron emission tomography combined with computed tomography (PET/CT) staging is controversial. PATIENTS AND METHODS Patients with newly diagnosed DLBCL who underwent both staging PET/CT and BMB were retrospectively identified in British Columbia, Aalborg, and Copenhagen. Original written PET/CT and pathology reports were retrospectively reviewed to determine Ann Arbor stage and outcomes, with and without the contribution of BMB. RESULTS A total of 530 patients were identified: 146 (28%) had focal bone marrow (BM) lesions on PET/CT and 87 (16%) had positive BMB. Fifty-two of 146 patients (36%) with positive PET/CT had a positive BMB [39 DLBCL, 13 indolent non-Hodgkin lymphoma (iNHL)], while 35 of 384 patients (9%) with negative PET/CT had positive BMB (12 DLBCL, 23 iNHL). BMB upstaged 12/209 (6%) of stage I/II patients to stage IV, although this was the case for only 3 (1%) patients with DLBCL in the BMB. PET/CT identified BM involvement by BMB with sensitivity 60%, specificity 79%, positive predictive value 36%, and negative predictive value 91%. Concordant histological involvement of the BM by DLBCL was associated with worse overall survival and progression-free survival than discordant or no involvement in univariate and multivariate analyses. CONCLUSIONS In patients with DLBCL, staging PET/CT can miss BM involvement with concordant DLBCL (less common) or discordant iNHL (more common). Routine BMB does not add relevant diagnostic or prognostic value over PET/CT alone in the majority of patients with DLBCL.

Improving Revised International Prognostic Scoring System Pre-Allogeneic Stem Cell Transplantation Does Not Translate Into Better Post-Transplantation Outcomes for Patients with Myelodysplastic Syndromes: A Single-Center Experience

The natural history of patients with myelodysplastic syndromes (MDS) is variable. The Revised International Prognostic Score (IPSS-R) is commonly used in practice to predict outcomes in patients with MDS at both diagnosis and before hematopoietic stem cell transplantation (HSCT). However, the effect of change in the IPSS-R before allogeneic HSCT with chemotherapy or hypomethylating agents on post-transplantation outcomes is currently unknown. We assessed whether improvement in IPSS-R prognostic score pre-HSCT would result in improvement in clinical outcomes post-HSCT. Secondary goals included studying the effect of prognostic factors on post-transplantation survival. All patients with MDS who underwent allogeneic HSCT at the Leukemia/BMT Program of British Columbia between February 1997 and April 2013 were included. Pertinent information was reviewed from the program database. IPSS-R was calculated based on data from the time of MDS diagnosis and before HSCT. Outcomes of patients who had improved IPSS-R pre-HSCT were compared with those with stable or worse IPSS-R. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method, with P values determined using the log-rank test. Hazard ratios were calculated using multivariable Cox proportional hazards regression models to study the effects of the prognostic variables on OS and EFS. A total of 138 consecutive patients were included. IPSS-R improved in 62 of these patients (45%), worsened in 23 (17%), remained stable in 41 (30%), and was unknown in 12 (9%). OS was not statistically different across the improved, worsened, and stable groups (30% versus 22% versus 40%, respectively; P = .63). The cumulative incidences of relapse and nonrelapse mortality at 5 years were 28.4% (95% confidence interval [CI], 21.1 to 36.1) and 31.6% (95% CI, 23.8 to 39.7), respectively. The rate of relapse was 23% in patients with <5% blasts at the time of HSCT, 69% in those with 5% to 20% blasts, and 66% in those with >20% blasts (P = .0004). In the entire cohort OS was 34% and EFS was 33%. There was no significant difference in outcomes between patients who received myeloablative conditioning and those who received nonmyeloablative conditioning before HSCT (OS, 34% and 39%, respectively; P = .63 and EFS, 34% and 32%, respectively; P = .86). OS was not statistically different among patients with improved, worsened, or stable IPSS-R. On multivariate analysis, only 3 factors were associated with OS: cytogenetic risk group at diagnosis, blast count at transplantation, and the presence or absence of chronic graft-versus-host disease. Improving IPSS-R before HSCT does not translate into better survival outcomes. Blast count pretransplantation was highly predictive of post-transplantation outcomes.

Peripheral T-Cell Lymphoma, Not Otherwise Specified: A Review of Current Disease Understanding and Therapeutic Approaches

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), corresponds with a heterogeneous group of mature T-cell lymphomas. Recent gene expression profiling studies have identified at least two molecular subgroups (GATA3 and TBX2). Standard treatment and outcomes remain poor. High-dose chemotherapy with autologous stem cell transplantation is incorporated into primary therapy for young fit patients but remains ineffective for most and has not been tested in a randomized study. Several novel agents have been approved for use in relapsed/refractory PTCLs, and although response rates are modest for most, durable remissions have been reported. Selecting rationale combinations and incorporating predictive biomarkers will be important moving forward to improve outcomes in patients with PTCL.

Practical Management of Castleman's Disease

Castlemans disease (CD) is a rare lymphoproliferative disorder that is most commonly present in multicentric (MCD) form in association with HIV infection. Interleukin-6 (IL-6) and human herpesvirus-8 (HHV-8) play major roles in MCD pathogenesis. Important treatment options have recently become available, particularly with the introduction of IL-6 and IL-6 receptor inhibitors for the treatment of HIV-negative patients with MCD. Though advances in therapy may improve outcomes in some patients, the prognosis remains guarded, and a stratified approach to the management of MCD is needed.

The standard, revised and simplified international prognostic index reliably predict outcome in patients with PET/CT-staged DLBCL treated with R-chop

151 Table CD3 P ≥ 50 CD4 P ≥ 50 CD8 P ≥ 50 CD3/B-cell P ≥ 50 CD4/CD8 P ≥ 50 CD4 TFH/CD4 + P ≥ 75 Age (%) <60 years 39 34 29 21 55 21 ≥60 years 59 56 57 43 43 39 Histological grade (%) 1–2 45 43 35 27 58 29 3 89 67 89 67 0 11 Bulky disease (%) No 57 53 46 60 46 23 Yes 22 17 33 11 56 29 Extranodal (%) ≤1 58 52 51 58 47 23 >1 21 21 21 26 53 29 Leukemic phase (%) No 56 50 48 32 60 22 Yes 10 10 10 0 46 25 182 Poster Presentations resistance. Immune cells in the lymphoma tumour microenvironment have been implicated in disease progression (Dave et al., NEJM 2004) and may play a role in transformation. We recently discovered that expression of the inhibitory receptor PD-1 was associated with suppressed cytokine signalling in FL tumour-infiltrating T cells (Myklebust et al., Blood 2013). Furthermore, it has been suggested that PD-1 int cells are the truly exhausted T cells and that PD-1 high cells are normal T follicular helper cells (TFH) (Yong et al., Blood Cancer J 2015). Antibody immunotherapy targeting PD-1 has shown significant promise in aggressive malignancies (Topalian et al., NEJM 2012), suggesting that exhausted T cells can regain functionality, including anti-tumour effects. Methods: Three mass cytometry (CyTOF) panels were designed to detect 30 markers per cell and used to characterize FL tumour biopsies (n = 9) and human tonsils. In the first panel, inhibitory and co-stimulatory receptors were quantified across 5 major T-cell subsets and maturation stages (Nicholas and Greenplate et al., manuscript in preparation). In the second panel, key surface markers were combined with antibodies to detect 12 phosphoproteins to correlate signalling responses with inhibitory receptor profiles. The last panel was designed to characterize healthy and malignant B cells. The dimensionality-reduction tool viSNE was used to analyse the high-dimensional mass cytometry data. Fluorescent flow panels were used in parallel to measure 9 inhibitory receptors in selected T-cell subsets. Results: viSNE analysis of 23 surface markers revealed a high degree of phenotypic similarity between T cells infiltrating FL and T cells in tonsils. In contrast, viSNE characterized the significant phenotypic differences between malignant B cells and healthy B cells within the same tumour. PD1 + T cells from FL samples displayed reduced cytokine signalling compared to PD1 cells, confirming previous results. TFH cells were identified as CXCR5 hi ICOS + CD4 memory T cells. Among the ICOS + cells in tonsils, a distinct CXCR5 population was identified with intermediate PD1 expression, suggesting an exhausted phenotype. These cells expressed less TIGIT, BTLA and LAIR1 than TFH but contained a subpopulation of TIM3 + cells that was not seen within the TFH population. Conclusions: Striking similarities in phenotype and signalling response of the T cells infiltrating FL tumours and T cells from healthy tonsil observed by mass cytometry suggest active immune responses in these tissues. These results provide further support for characterizing relationships between receptor signalling and T cell function and for researching into combination immunotherapies for FL focused on modulating adaptive immune responses. 151 T-CELL SUBPOPULATIONS QUANTIFIED BY FLOW CYTOMETRY IN LYMPH NODE CELL SUSPENSIONS IDENTIFY A GROUP OF PATIENTS WITH FOLLICULAR LYMPHOMA WITH FAVORABLE OUTCOME L. Magnano 1 , J. Carreras 2 , A. Martinez 2 , A. Martinez-Trillos 1 , J. Rovira 1 , I. Dlouhy 1 , E. Gine 1 , T. Bauman 1 , O. Balague 2 , E. Campo 2 , N. Villamor 3 , A. López-Guillermo 1 . 1 Hematología, Hospital Clinic de Barcelona, Barcelona, Spain, 2 Pathology Department, Hospital Clinic de Barcelona, Barcelona, Spain, 3 Hematopathology Unit, Hospital Clinic de Barcelona, Barcelona, Spain. Introduction: Tumour microenvironment plays an important role in the behaviour of follicular lymphoma (FL). By gene expression and immunohistochemistry, an increase in macrophages has been associated with poor outcome, while an increase in T cells is associated with good prognosis. The aim of the study was to explore the prognostic impact of subpopulations of T cells using flow cytometry and to identify different groups of risk in FL patients. Methods: Seventy-five patients (36 men/39 women, median age 60 years) diagnosed of FL (grades 1–2, 87%; grade 3, 13%) between 1984 and 2009 (median follow-up of 6.5 years) with sample at diagnosis were included in the present study. In 41 cases, T-cell staining were semiquantitatively analysed by immunohistochemical (IHC), including their distribution (intra, inter or perifollicular). T-cell populations from lymph node were quantified by multiparametric flow cytometry in cell suspensions in all cases. The percentage of B-cells, CD3 + , CD4 + , CD8 + , CD57 + , CD4TFH cells (double staining CD4 + CD57 + ), as well as the ratio T/B-cells, CD3 + /CD4 + , CD3 + /CD8 + , CD4 + /CD8 + and CD4TFH/CD4 + were analysed and correlated with initial features and outcome. Copyright

Human immunodeficiency virus-associated multicentric Castleman disease refractory to antiretroviral therapy: clinical features, treatment and outcome

Abstract Human immunodeficiency virus (HIV)-associated multicentric Castleman disease (MCD) is a lymphoproliferation associated with human herpes virus-8 (HHV-8). Optimal treatment in patients not responding to antiretroviral therapy (ART) is undefined. We report 12 patients with ART refractory HIV-MCD. Patients with HIV-MCD were identified and baseline characteristics, treatment and outcome considered. Median CD4 count at HIV-MCD diagnosis was 295 (60–950) cells/mL. All patients had waxing and waning systemic symptoms, lymphadenopathy and/or splenomegaly, with non-Hodgkin lymphoma (NHL) in three. Treatment included: anti-HHV-8 therapy, n = 8; alone, n = 4; with systemic chemotherapy (CT) ± immunotherapy (IT), n = 4; CT ± IT only, n = 2. Initial median HHV-8 viral load (VL) was 7 × 104 copies/mL and at follow-up < 40 in 6/7 survivors; and 403–7.2 × 106 in 4/5 who died. One patient developed NHL despite an HHV-8 VL < 40. HIV-MCD is challenging to treat. Suppression of plasma HHV-8 VL did not prevent development of NHL. Anti-HHV-8 therapy should probably be considered adjunctive to cytotoxic therapies.