Key Points• Population-based data show a favorable outcome with upfront autologous stem cell transplantation in PTCL.• The addition of etoposide to CHOP was associated with favorable PFS in patients #60 years with PTCL.Peripheral T-cell lymphomas (PTCLs) are rare lymphomas with mostly poor outcome with current treatment. The addition of etoposide to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and upfront consolidation with autologous stem cell transplantation (auto-SCT) have shown promising results but have never been tested in randomized trials. As a complement to retrospective analyses of clinical trials, we aimed at analyzing prognostic factors and outcome in an unselected, population-based cohort. Through the Swedish Lymphoma Registry, we identified 755 PTCL patients diagnosed during a 10-year period. In addition to International Prognostic Index factors, male gender was associated with an adverse overall survival (OS) (hazard ratio [HR], 1.28; P 5 .011) and progression-free survival (PFS) (HR, 1.26; P 5 .014). In an intention-to-treat analysis in 252 nodal PTCL and enteropathy-associated T-cell lymphoma patients (excluding anaplastic lymphoma kinase-positive anaplastic large cell lymphoma), upfront auto-SCT was associated with a superior OS (HR, 0.58; P 5 .004) and PFS (HR, 0.56; P 5 .002) compared with patients treated without auto-SCT. The addition of etoposide to CHOP resulted in superior PFS in patients £60 years (HR, 0.49; P 5 .008). This study is the largest population-based PTCL cohort reported so far and provides important information on outcome in PTCL outside the setting of clinical trials. (Blood. 2014;124(10):1570-1577

Key Points• CNS involvement at relapse/ progression in PTCL occurred at a frequency similar to what is seen in aggressive B-cell lymphomas.• Outcome after relapse is generally very poor in patients with PTCL and is not significantly altered by presence of CNS involvement at relapse.Central nervous system (CNS) relapse in non-Hodgkin lymphoma (NHL) carries a very poor prognosis. Risk factors and outcome have been studied in aggressive B-cell lymphomas, but very little is known about the risk in peripheral T-cell lymphoma (PTCL). We aimed at analyzing risk factors for CNS involvement at first relapse or progression, as well as the outcome of these patients, in a large population-based cohort of patients with PTCL. Twenty-eight out of 625 patients (4.5%) developed CNS disease over time. In multivariable analysis, disease characteristics at diagnosis independently associated with an increased risk for later CNS involvement were involvement of more than 1 extranodal site (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.07-6.29; P 5 .035) and skin (HR, 3.51; 95% CI, 1.26-9.74; P 5 .016) and gastrointestinal involvement (HR, 3.06; 95% CI, 1.30-7.18; P 5 .010). The outcome of relapsed/refractory patients was very poor, and CNS involvement was not associated with a significantly worse outcome compared with relapsed/refractory patients without CNS involvement in multivariable analysis (HR, 1.6; 95% CI, 0.96-2.6; P 5 .074). The results from the present study indicate that CNS relapse in PTCL occurs at a frequency similar to what is seen in aggressive B-cell lymphomas, but the poor outcomes in relapse are largely driven by systemic rather than CNS disease. (Blood. 2015;126(1):36-41)

Introduction Disease relapse involving the central nervous system (CNS) carries a dismal prognosis in patients with aggressive lymphoma. Risk factors for CNS-relapse have included involvement of lymphoma at specific anatomical sites, proliferation rate and high tumor burden. The risk and importance of CNS-relapse in peripheral T-cell lymphomas (PTCL) has been very little studied. So far, the only study focusing on CNS-relapse in PTCL found elevated LDH and paranasal sinus involvement to be independent risk factors and that CNS-relapse was associated with an inferior survival. Recently, several studies have highlighted the dismal prognosis of relapsed PTCL in general. In this study we aimed at analyzing risk factors for CNS involvement in first relapse and the outcome of these patients, in a large population-based cohort of PTCL patients. Materials and methods Through the Swedish Lymphoma Registry we identified all adult (>18 years) patients diagnosed with PTCL between January 1st 2000 and December 31st 2009. Primary cutaneous, primary leukemic types and T-cell lymphoblastic lymphoma were excluded. Information on first relapse was collected from patient files retrospectively after informed consent. Results Out of 755 patients identified through the registry, 10 patients had CNS involvement at diagnosis and were excluded from further analyses. Data on first relapse was available for 618, and among these 369 patients experienced relapse or progression. Thirty-one patients (5.0 %) experienced progression or relapse involving the CNS after a median time of 4.3 months (range 1.1-45 months) from diagnosis. Thirteen patients experienced an isolated CNS relapse/progression and 18 as part of a systemic relapse. Sixteen patients relapsed after responding to primary therapy (10 CR, 6 PR), and 15 patients with refractory disease had CNS-progression (1 SD, 14 PD). Histologic subtypes among the 31 patients were ALK-positive anaplastic large cell lymphoma (ALCL) (n=3), ALK-negative ALCL (n=3), ALK-unknown ALCL (n=1), angioimmunoblastic T-cell lymphoma (n=3), peripheral T-cell lymphoma NOS (n=13), enteropathy-associated T-cell lymphoma (n=3), NK/T-cell lymphoma nasal type (n=1), hepatosplenic T-cell lymphoma (n=1) and unclassified T-cell lymphoma (n=1). All 31 patients had received chemotherapy with curative intent and 6 received intrathecal prophylaxis. In multivariable analysis, the presence of B-symptoms (HR 2.79 95% CI 1.14-6.82, p=0.024), >1 extranodal site of disease (HR 3.28[1.41-7.64], p=0.006) and skin involvement (HR 3.06 [1.10-8.49], p=0.032) were independent risk factors for CNS relapse. Median survival for patients with CNS involvement at relapse or progression was 3.3 months (range 0-124) compared to 3.7 (range 0-129) for patients without CNS involvement and CNS involvement was not a risk factor for OS after relapse/progression (HR 1.08 [0.73-1.59], p=0.700). For relapsing patients only age was predictive of inferior survival (1.014 [1.002-1.027], p=0.026) whereas in patients with primary refractory disease, male gender predicted inferior survival (2.93 [1.54-5.58], p=0.001) and angioimmunoblastic T-cell lymphoma was associated with better survival (0.41 [0.18-0.95], p=0.037). Conclusions CNS involvement, isolated or as part of a systemic first relapse, occurred in 5% of the patients in our series, which is similar to the incidence in larger series dominated by B-cell lymphomas. In our cohort, B-symptoms, >1 extranodal site of disease and skin involvement were independent predictors for CNS-relapse. The outcome of relapsed patients was very poor in general, and CNS-involvement did not convey worse outcome compared to patients with systemic relapse only. With current treatment strategies the uncommon CNS-relapses seem to be a problem of lower magnitude compared to the frequent systemic relapses. Future improvements in the treatment of PTCLs could possibly increase the importance of identifying patients at risk for CNS-relapse, and our study provides data on this poorly described complication. Disclosures No relevant conflicts of interest to declare.

Introduction Comorbidity has repeatedly been established to have a negative impact on the survival of patients with cancer, but it has not been investigated in peripheral T-cell lymphomas (PTCLs). The impact of comorbidity depends on the prognosis of the malignancy, and because PTCLs are aggressive diseases that generally respond less well to treatment compared to aggressive B-cell lymphomas, we aimed to investigate how comorbidities affect outcome in a large population-based cohort of PTCL patients. Materials and methods Through the Swedish Lymphoma Registry all patients diagnosed with T-cell lymphomas between 2000 and 2009 were identified. After informed consent, data on comorbidity at the time of diagnosis was collected from the patient records and classified according to the Charlson Comorbidity Index (CCI). All cases of diabetes mellitus were awarded 1 CCI point because complications to diabetes mellitus could not reliably be evaluated from available medical records. Non-melanoma skin tumors were not recorded as malignancies. Results In total 755 patients with non-cutaneous, non-leukemic PTCL were identified. Comorbidity data was available for 676 of the 755 patients (90%). Four-hundred twenty-five (56%) of the patients had no co-morbidity, while 267 (35%) had CCI scores between 1 and 7 points. The 5-year overall survival (OS) rates for patients with CCI 0, 1 and ≥2 were 41%, 23% and 12 % respectively. There was no significant difference in survival of patients with CCI 2 or higher. Individual CCI factors with prognostic impact on OS in univariable analysis were previous malignancy (Hazard ratio [HR] 1.68, p=0.001), active malignancy (HR 2.04, p<0.001), renal failure (HR 5.56, p<0.001), liver disease (HR 2.66, p=0.018), peptic ulcer (HR 1.82, p=0.020), diabetes mellitus (HR 1.85, p<0.001), myocardial infarction (HR 1.62, p=0.001), congestive heart failure (HR 2.17, p<0.001), stroke (HR 1.74, p=0.005) and autoimmune disease (HR 1.50, p=0.034). The cause of death was known in 451 patients and lymphoma related death was more common among patients with CCI 0 (82%) than with CCI 1 (69%) or CCI ≥2 (65%) (p=0.008 and p=0.001 respectively). In multivariable analysis, comorbidity was an independent negative factor for both OS and progression-free survival (PFS). Among patients receiving chemotherapy (N=551) the presence of comorbidity together with age, male gender, stage III-IV, LDH>ULN, extranodal involvement >1, WHO PS >1, gastrointestinal involvement and NK/T-cell, nasal type lymphoma were independent risk factors for OS with HR 1.46 for CCI 1 (p=0.004) and HR 1.76 for CCI ≥2 (p<0.001). The impact of comorbidity was age dependent as patients above the median age of the cohort (>67 years) had inferior OS (HR 1.64, p=0.006) and PFS (HR1.51, p=0.027) only if they presented with CCI ≥2. Up-front autologous stem cell transplantation (auto-SCT) was planned in 154 out of 755 patients. Comorbidity data was available in 149, and auto-SCT as part of first-line therapy was performed in 101 (68%) of these patients. In this group comorbidities were uncommon but diabetes mellitus was most frequent (n=10) with an impact on OS (HR 3.31, p=0.01, n=10) and PFS (HR 2.86, p=0.003) and was an independent risk factor in multivariable analysis (data not shown). Using the CCI, instead of individual comorbidities, independent prognostic factors for OS were age (HR 1.028, p=0.017), skin involvement (HR 2.29, p=0.016) and CCI (CCI 1 HR 1.94, p=0.019 and CCI ≥2 HR 3.67, p=0.004). For PFS, skin involvement (HR 3.70, p<0.001) and CCI (CCI 1 HR 1.80, p=0.039 and CCI ≥2 HR 3.56, p=0.012) but not age, were independent adverse prognostic factors, while ALKneg ALCL histologic subtype was associated with favorable PFS (HR 0.49, p=0.028). There was no difference in the proportion of patients with planned auto-SCT actually performed between the CCI groups, although there were only 5 patients with CCI ≥2 in this group. Conclusions Our data demonstrates that even though PTCLs are aggressive diseases with a substantial proportion of cases responding poorly to chemotherapy, comorbidity has an important impact on outcome, not the least in patients planned for up-front auto-SCT. Despite medical advances in the treatment of several of the conditions included in the score, the CCI still seems to be a useful tool to capture comorbidity. Disclosures No relevant conflicts of interest to declare.