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Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1–3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

Although methotrexate (MTX) is the most widely used therapy for central nervous system (CNS) prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the optimal regimen remains unclear. We examined the efficacy of different prophylactic regimens in 585 patients with newly diagnosed DLBCL and high-risk for CNS relapse, treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens from 2001 to 2017, of whom 295 (50%) received prophylaxis. Intrathecal (IT) MTX was given to 253 (86%) and high-dose MTX (HD-MTX) to 42 (14%). After a median follow-up of 6.8 years, 36 of 585 patients relapsed in the CNS, of whom 14 had received prophylaxis. The CNS relapse risk at 1 year was lower for patients who received prophylaxis than patients who did not: 2% vs. 7.1%. However, the difference became less significant over time (5-year risk 5.6% vs. 7.5%), indicating prophylaxis tended to delay CNS relapse rather than prevent it. Furthermore, the CNS relapse risk was similar in patients who received IT and HD-MTX (5-year risk 5.6% vs. 5.2%). Collectively, our data indicate the benefit of MTX for CNS prophylaxis is transient, highlighting the need for more effective prophylactic regimens. In addition, our results failed to demonstrate a clinical advantage for the HD-MTX regimen.

Pre-transplantation 18F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) for patients with relapsed or refractory Hodgkin's lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE). In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkin's lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m2 in combination with mesna 5000 mg/m2 continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m2 every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with ClinicalTrials.gov, number NCT01508312, and is no longer accruing patients. Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkin's lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13–40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60–86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53–85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62–89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3–4 adverse events including hyperglycaemia (two [4%] patients, grade 3), nausea (one [2%], grade 3), hypoglycaemia (one [2%], grade 3 and one [2%], grade 4), and hypocalcaemia (one [2%], grade 3 and one [2%], grade 4). PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkin's lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT. Seattle Genetics.

As the survival of patients with mantle cell lymphoma (MCL) continues to improve, patients are increasingly being treated with multiple regimens. However, outcome after each line remains poorly characterized in the modern era. To address this knowledge gap, we retrospectively studied 404 consecutive MCL patients who were managed between 2000 and 2014 at Memorial Sloan Kettering Cancer Center. Histologic diagnosis was centrally confirmed, and patients were followed longitudinally from diagnosis throughout their disease course. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan–Meier method. The median OS and PFS after first-line treatment were 9.7 and 4.0 years, respectively. After second-line therapy, the median OS and PFS were 41.1 and 14.0 months, third line were 25.2 and 6.5 months, and fourth line were 14.4 and 5.0 months. In patients less than 65 years, stem cell transplant (SCT)-based frontline regimens were associated with improved PFS compared with non-SCT regimens (median PFS: 86.2 versus 40.0 months; P < 0.01), with a trend toward longer OS (median OS: 165.0 versus 120.0 months; P = 0.06). Early treatment failure after first-line regimens was associated with worse OS (5.9 versus 2.5 years; P < 0.01). Our study should facilitate establishing proper endpoints for future clinical trials using novel treatment approaches.

Background/Objectives: Intensive chemotherapy is the cornerstone of lymphoma treatment but often leads to severe chemotherapy-induced thrombocytopenia (sCIT), resulting in treatment delays, reduced dose intensity, and the need for transfusions. While granulocyte colony-stimulating factors (G-CSFs) are commonly used to manage neutropenia, the use of thrombopoietic growth factors has not been adequately studied. Methods: This phase I dose-finding study evaluated the use of weekly romiplostim as prophylaxis for recurrent sCIT in patients undergoing chemotherapy for lymphoma. Eligible patients were those treated with a 21-day chemotherapy cycle who previously experienced sCIT, thus serving as their own “controls”. sCIT was defined as one of the following: (A) a platelet count (PLT) <50 × 109/L on day 1 of the subsequent cycle, leading to delay or dose reduction in chemotherapy, or (B) grade 4 thrombocytopenia (<25 × 109/L) and/or (C) platelet transfusion for bleeding. The primary endpoints were the incidence of sCIT and the rate of romiplostim-associated-adverse-events, with thromboembolic complications being an event of special interest. Results: Nine patients with sCIT requiring a PLT transfusion on the prior treatment cycle were treated across three dose schedules. The phase 2 recommended schedule was defined as a starting dose of 3–5 mcg/kg based on the baseline PLT count, with weekly adjustments for counts <150 × 109/L and >450 × 109/L. Romiplostim prevented recurrent grade 4 thrombocytopenia in 47% of the chemotherapy cycles and averted recurrent transfusion in 65% of cycles. Notably, low starting doses, as used in solid malignancies, were insufficient, leading to recurrent thrombocytopenia. Conclusions: Romiplostim was well-tolerated, with no thromboembolic events, and allowed most patients to complete their chemotherapy on schedule at full dose intensity.

Introduction: Immune evasion through inhibition of effector T cells is a key survival mechanism of lymphoma cells. We hypothesized that reinstating effector T cell activity through concurrent inhibition of the PD1/PD-L1 axis and of Treg activity will result in a synergistic anti-tumor effect with an acceptable toxicity profile. Methods: Phase I multi-institutional NCI-ETCTN trial aimed to evaluate the safety and tolerability of the combination of mogamulizumab and pembrolizumab in relapsed or refractory non-Hodgkin lymphoma. The study used a 3 + 3 design. Treatment consisted of mogamulizumab 1 mg/kg on days 1, 8, and 15 of cycle 1, followed by 1.5 mg/kg on day 1 of each subsequent 21-day cycle in combination with pembrolizumab 200 mg on day 1 of each cycle. A de-escalation level was defined as a 50% reduction in the dose of mogamulizumab (registered in clinicaltrials.gov NCT03309878). Results: The study was discontinued early, after treating seven patients (two angioimmunoblastic T cell lymphoma, four transformed follicular lymphoma, and one diffuse large B cell lymphoma of germinal center subtype) for concerns of futility and non-tolerability. Only two patients completed the first two cycles of treatment. Three patients presented with an early progression and three withdrew consent in the setting of general deterioration with clinically suspected progression. All six patients expired shortly after withdrawal from the study. The remaining patient experienced stress cardiomyopathy during the third cycle and was taken off the study. Discussion: In striking difference to the observation in solid malignancies, the combination of mogamulizumab with pembrolizumab was associated with low tolerability and suspected hyper-progression in patients with lymphoma.

Background/Objectives Epstein-Barr Virus (EBV) is a ubiquitous virus associated with a variety of diseases including cancers. Evidence has emerged that the C promoter is methylated in many EBV-associated malignancies, whereas in free virion DNA it is unmethylated. We have developed and evaluated a methylation-specific PCR assay for the EBV C Promoter (MSPCP) that can be applied to human biological specimens to quantify EBV methylation. Methods Two sets of methylation-specific primers were designed to anneal to bisulfite-converted DNA sequences with 3 CpGs in the forward primer binding site, and 2 CpGs in the reverse primer binding site. We evaluated this method in synthetic oligonucleotides, DNA extracted from cell lines, virion supernatants, and a variety of clinical specimens. EBV methylation of Cp, as measured by MSPCP, was validated with two orthogonal methods in select samples. Results In contrived samples, this method had a linear range between 0–100% methylation. Application of this assay to DNA extracted from 11 formalin-fixed paraffin-embedded biopsy specimens showed high-level C promoter methylation in EBV-associated tumors (94–100%) but not in EBV-associated lymphoid hyperplasia. High-level EBV methylation was also detected in cell-free DNA extracted from the plasma of 13 patients with EBV-associated Hodgkin lymphoma. In contrast, EBV methylation was either not-detected, or detected at very low levels, in saliva from 25 adults in a general university population consistent with the presence of virion DNA. Conclusions MSPCP is a simple, rapid and accurate method that characterizes the methylation status of the EBV C promoter, which may be useful in a variety of research and clinical settings.

Characteristics Overalla Single lesiona Multifocala N = 44 N = 31 N = 13 Median Age 75 (40, 96) 76 (40, 89) 72 (43, 96) Gender  F 21 (48%) 15 (48%) 6 (46%)  M 23 (52%) 16 (52%) 7 (54%) Race  White 33 (87%) 25 (93%) 8 (73%)  Asian 3 (8%) 1 (4%) 2 (18%)  African American 1 (3%) 1 (4%) 0 (0%)  Other 1 (3%) 0 (0%) 1 (9%)  Unknown 6 4 2 Ethnicity  Not hispanic 38 (97%) 27 (100%) 11 (92%)  Hispanic or latino 1 (3%) 0 (0%) 1 (8%)  Unknown 5 4 1 B symptoms 0 (0%) 0 (0%) 0 (0%) ECOG PS  0 28 (64%) 21 (68%) 7 (54%)  1 14 (32%) 8 (26%) 6 (46%)  2/3 2 (4.5%) 2 (6.5%) 0 (0%) Skin site  Lower extremity 18 (41%) 10 (32%) 8 (62%)  Other site 26 (59%) 21 (68%) 5 (38%) Bulky mass (>5 cm) 5 (14%) 3 (13%) 2 (15%)  Unknown 7 7 0 White blood cells * 1000/microL 7.0 (2.6, 12.6) 6.8 (4.3, 12.6) 7.4 (2.6, 10.8)  Unknown 3 2 1 Hemoglobin, g/dL 13.4 (9.9,16.1) 13.5 (11.0, 16.1) 12.9 (9.9, 15.0)  Unknown 4 3 1 Platelets * 1000/microL 218 (126, 453) 199 (126, 383) 234 (175, 453)  Unknown 3 2 1 Albumin, g/dL 4.2 (3.5, 27.0) 4.2 (3.8, 27.0) 4.2 (3.5, 4.7)  Unknown 4 3 1 Elevated LDH 8 (19%) 7 (23%) 1 (8%)  Unknown 2 1 1 IPI  0/1 32 (76%) 22 (73%) 10 (83%)  2 9 (21%) 7 (23%) 2 (17%)  3 1 (2%) 1 (3%) 0 (0%)  Unknown 2 1 1 CNS-IPI  0/1 30 (71%) 21 (70%) 9 (75%)  2/3 12 (29%) 9 (30%) 3 (25%)  Unknown 2 1 1 Additional cancers 23 (52%) 16 (52%) 7 (54%) Additional skin cancers 15 (34%) 10 (32%) 5 (38%) First-line Treatment  RT 11 (25%) 9 (29%) 2 (15%)  Chemotherapy 15 (34%) 10 (32%) 5 (38%)  Chemotherapy + RT 15 (34%) 10 (32%) 5 (38%)  Other 3 (7%) 2 (6.5%) 1 (8%) First-line CNS prophylaxis 6 (14%) 3 (10%) 3 (23%) PS performance status, LDH lactate dehydrogenase, IPI international prognostic index, CNS central nervous system, RT radiation therapy. aValues reported as n (%) or as median (range). All 44 patients were evaluable for response, with an overall response rate (ORR) of 86% and complete response (CR) rate of 84%. There was no significant difference in response rates (p = 0.13) among the RT, CHT and CMT groups. No significant differences in response rates (p = 0.4) or PFS (p = 0.8) (supplemental tables 3, 4) were observed between the two groups, while a trend toward improved OS was noted in patients with a single lesion, with a median OS of 14 years (95%CI, 9.9-NR), compared to 4.6 years (95%CI, 2.6-NR) for those with multifocal disease (p = 0.11, supplemental table 5 and supplemental Fig. 1).

Between 1998 and 2009, a total of 295 patients (median age 58, 53% females) with newly diagnosed early-stage follicular lymphoma (FL) were managed at Memorial Sloan Kettering Cancer Center. Approximately half of patients (137, 46%) underwent initial observation and half (158, 54%) immediate treatment: radiation alone (n = 108), systemic treatment alone (n = 29), or combined modality treatment (n = 21). Median follow-up was 8.4 years (range 0.3–17.2), and 10-year overall survival (OS) was 87.2%. OS was similar between initially-observed and immediately-treated patients (hazard ratio [HR]: 1.25, 95% CI: 0.67–2.36, p = 0.49). For patients receiving radiation alone, 5-year OS was 98.0%. Patients selected for systemic therapy alone had high-risk baseline features and had shorter OS than patients treated with radiation alone (HR 3.38, 95% CI 1.29–8.86, p = 0.01). Combined modality treatment did not yield superior survival compared with radiation alone (P > 0.05) but was associated with better progression-free survival (HR 0.36, 95% CI 0.14–0.90, p = 0.03). The rate of transformation increased steadily over time and was 4.2% at 5 years and 10.8% at 10 years. This modern-era analysis rationalized the role of initial observation in patients with early-stage FL although patients receiving radiation therapy also demonstrate excellent outcome.

Human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma (ATLL) has a very poor prognosis, despite trials of a variety of different treatment regimens. Virus expression has been reported to be limited or absent when ATLL is diagnosed, and this has suggested that secondary genetic or epigenetic changes are important in disease pathogenesis. We prospectively investigated combination chemotherapy followed by antiretroviral therapy for this disorder. Nineteen patients were prospectively enrolled between 2002 and 2006 at five medical centers in a phase II clinical trial of infusional chemotherapy with etoposide, doxorubicin, and vincristine, daily prednisone, and bolus cyclophosphamide (EPOCH) given for two to six cycles until maximal clinical response, and followed by antiviral therapy with daily zidovudine, lamivudine, and alpha interferon-2a for up to one year. Seven patients were on study for less than one month due to progressive disease or chemotherapy toxicity. Eleven patients achieved an objective response with median duration of response of thirteen months, and two complete remissions. During chemotherapy induction, viral RNA expression increased (median 190-fold), and virus replication occurred, coincident with development of disease progression. EPOCH chemotherapy followed by antiretroviral therapy is an active therapeutic regimen for adult T-cell leukemia-lymphoma, but viral reactivation during induction chemotherapy may contribute to treatment failure. Alternative therapies are sorely needed in this disease that simultaneously prevent virus expression, and are cytocidal for malignant cells.