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Treatments for adults with newly-diagnosed acute lymphoblastic leukemia (ALL) may be prohibitively toxic and/or resource-intense. To address this, we performed a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH). Imatinib or dasatinib was added for Ph + disease; rituximab was added when CD20+. Fifty-three patients were evaluable: 28 with Ph + disease, and 25 with Ph-. All patients had ≥1 high-risk clinical feature. Measurable residual disease-negativity by multiparameter flow cytometry within 4 cycles was achieved in 71% in patients with Ph + ALL and 64% in Ph - ALL. Median overall survival (OS) was 49 months, with a 2-year OS of 71%. Median relapse-free survival (RFS) in the 47 patients that attained morphologic remission was 24 months, with a 2-year RFS of 57%. Early mortality was 2%. In summary, DA-EPOCH yields deep and durable remissions in adults with ALL comparable to some resource-intense strategies but with a low rate of treatment-related death.

Background: Potential involvement of the central nervous system (CNS) by acute lymphoblastic leukemia is typically evaluated by a conventional cytospin (CC) of cerebrospinal fluid (CSF). Multiparameter flow cytometry (MFC) is generally more sensitive and specific than morphology, but data to guide its use versus CC are limited., Methods: This study identified 92 patients who had MFC performed on their initial CSF specimen and received at least 4 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) as their initial treatment., Results: Eighteen (20%) were CSF+ by MFC at the baseline, and only 6 of these patients were positive by CC. In contrast, 0 of 51 patients who were negative by MFC and had CC available were positive by CC. Despite the receipt of significantly more intra-CSF chemotherapy (P < .001), the cumulative incidence of CNS relapse by MFC was 22% among CSF+ patients versus 5% among those who were CSF- (P = .044). No such association was observed between CNS relapse and CC results (P = .42). None of the 74 CSF- patients became CSF+ during their initial treatment despite being tested a median of 5 times (range, 2-10). CSF positivity by MFC was the factor most strongly associated with CNS relapse in a series of univariate Cox models (hazard ratio, 3.7; P = .067). The initial CSF status by MFC had no significant impact on overall or event-free survival., Conclusions: MFC of CSF is superior to CC of CSF in identifying adults at high risk for CNS relapse after treatment with hyperCVAD. Surveillance of CSF by MFC has limited utility., (© 2021 American Cancer Society.)

Background: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome., Methods: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621., Findings: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient., Interpretation: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions., Funding: Trillium Therapeutics., Competing Interests: Declaration of interests CQ reports research grants from Celgene; is a clinical investigator for Trillium Therapeutics, MiRagen, Bioniz, and Kyowa Kirin; and reports participation in advisory boards for Helsinn, miRagen, Bioniz, Trillium Therapeutics, and Kyowa Kirin. JAT reports research grants from Merck, Hoffmann-LaRoche, Pfizer, Five Prime, Novartis, Incyte, Trillium Therapeutics, and Xencor; and participation in advisory boards for Neoleukin, AVEO Oncology, and Regeneron. MHT reports research funding to their institution from Bristol Myers Squibb, Merck, Pharmacyclics, AstraZeneca, Eisai, Incyte, EMD Serono, Novartis, Seattle Genetics, AbbVie, Genentech, Eli Lilly, Roche, Acerta Pharma, Genzyme Corporation, and Pfizer; consulting or participation in advisory boards for Bristol Myers Squibb, Eisai, Novartis, Bayer, Sanofi/Genzyme, Array BioPharma, LOXO oncology, Blueprint Medicines, and Arqule; and participation in speakers' bureaus for Bristol Myers Squibb and Eisai. JAD reports speaker fees from Helsinn; and consultant fees from Regeneron. JMZ reports participation in advisory boards for Kyowa Kirin, Secura Bio, Mudi Pharma, Seattle Genetics, Legend Bio tech, and Ono Pharma; and research funding to their institution from Seattle Genetics, AbbVie, Karyopharm, and CRSPR. ARS has been a consultant for Acrotech, Bristol Myers Squibb-Celgene, Kyowa-Hakko-Kirin, and Portolla. SM has been a sub-investigator for Trillium Therapeutics, Bioniz, Kyowa Kirin, Affimed, Galderma, Soligenix, Helsinn, and Eisai; and been on the nurse advisory board for Kyowa Kirin. GHYL, PSP, RAU, NM, and YS report employment by and stock ownership in Trillium Therapeutics. OEA reports research grants from Trillium Therapeutics, Pfizer, and Kyowa Kirin; has been a clinical investigator for Trillium Therapeutics, Bioniz, Kyowa Kirin, Affimed, Galderma, Soligenix, Helsinn, and Eisai; and reports participation in advisory boards for Bioniz, Trillium Therapeutics, Kyowa Kirin, Medivir, and Almirall. CJ declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary end points were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced-stage disease. Eighty-one percent received anthracycline-based regimens, and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ≥60 years, Eastern Cooperative Oncology Group performance status >2, elevated C-reactive protein, and elevated β2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low-, intermediate-, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared with only 6% for patients with POD24 (P < .0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need, and novel therapeutic approaches are required., (© 2021 by The American Society of Hematology.)

Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035., (© 2021 by The American Society of Hematology.)

Introduction: We examined patient characteristics, treatments, and outcomes of patients with transformed mycosis fungoides (tMF) from COMPLETE: a large, multicenter, prospective cohort study of peripheral T-cell lymphoma patients in the United States., Methods: Patients with tMF were enrolled in COMPLETE at the time of transformation. For this analysis, we identified patients with tMF with completed baseline, treatment, and follow-up records. Median survival was assessed using Kaplan-Meier methodology., Results: Of the 499 patients enrolled in COMPLETE, 17 had tMF. Median age was 61; 53% were male, 9 had elevated lactate dehydrogenase, and 9 had lymph node involvement. Approximately one-quarter of the patients were African American and 47% had CD30+ disease. Median time to transformation was 53 months. All patients received systemic therapy, with 19% receiving concomitant radiotherapy. Most patients (87%) received single agents, including liposomal doxorubicin, pralatrexate, and gemcitabine. Eight patients (50%) had reported responses to therapy. Median survival was 18 months. One- and 2-year survival rates were 56% and 44%, respectively., Conclusions: tMF often expresses CD30 and presents with lymph node involvement. Responses have been seen with single agents, but survival remains poor. Novel treatment approaches are urgently needed to improve outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Extranodal natural killer (NK) T-cell lymphoma (ENKTL) is a unique clinicopathological entity, typically associated with poor survival outcomes. Most published data have come from east Asian study groups, with little information available from international cohorts. The effects of treatment advances on routine clinical practice across continental territories has not been clear. We aimed to improve understanding of the clinical characteristics and outcomes of patients with ENKTL., Methods: We did a substudy of patients with ENKTL from the T-cell Project, a global prospective cohort study. The T-cell Project registered consecutively diagnosed adults (>18 years) with newly diagnosed, untreated mature T-cell or NK lymphomas (WHO 2001 or 2008 classifications) from 74 centres in 13 countries (in Asia, Europe, North America, and South America). In total, 1695 patients with mature T-cell or NK lymphomas were enrolled between Oct 12, 2006 and Feb 28, 2018 in the T-cell Project. The first patient with ENKTL was enrolled on Feb 15, 2007, and the last on May 26, 2017. Data on baseline characteristics, first-line treatment, treatment response, and survival outcomes were recorded in a central database (locked March 30, 2019). The primary outcome was 5-year overall survival. The T-cell Project is registered on ClinicalTrials.gov, NCT01142674., Findings: 166 patients were diagnosed with ENKTL, comprising 11% of 1553 eligible registered cases and distributed across 40 participating centres in four continents. At a median follow-up of 44 months (IQR 20-61), overall survival at 5 years was 54% (95% CI 44-63) in patients with nasal disease (n=98) and 34% (27-46) in patients with extranasal disease (n=68)., Interpretation: To our knowledge, this study presents the largest international cohort of patients with ENKTL. We describe a clinically significant improvement in the survival of patients with ENKTL treated in routine clinical practice over the past decade, likely to be attributable to the increasing use of treatment protocols specific for ENKTL., Funding: The Fondazione Cassa di Risparmio di Modena, the Associazione Angela Serra per la Ricerca sul Cancro, the Fondazione Italiana Linfomi, Allos Therapeutics, Spectrum Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro, and the National Cancer Institute at the National Institutes of Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data., Objectives: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease., Methods: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days., Results: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months., Conclusions: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed., (© 2019 S. Karger AG, Basel.)

The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non-T-cell lymphoma. The overall response rate in all, non-T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035., (© 2019 by The American Society of Hematology.)

Single agents have demonstrated activity in relapsed and refractory (R/R) peripheral T-cell lymphoma (PTCL). Their benefit relative to combination chemotherapy remains undefined. Patients with histologically confirmed PTCL were enrolled in the Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) registry. Eligibility criteria included those with R/R disease who had received one prior systemic therapy and were given either a single agent or combination chemotherapy as first retreatment. Treatment results for those with R/R disease who received single agents were compared to those who received combination chemotherapy. The primary endpoint was best response to retreatment. Fifty-seven patients met eligibility criteria. At first retreatment, 46% (26/57) received combination therapy and 54.5% (31/57) received single agents. At median follow up of 2 years, a trend was seen towards increased complete response rate for single agents versus combination therapy (41% vs 19%; P = .02). There was also increased median overall survival (38.9 vs 17.1 months; P = .02) and progression-free survival (11.2 vs 6.7 months; P = .02). More patients receiving single agents received hematopoietic stem-cell transplantation (25.8% vs 7.7%, P = .07). Adverse events of grade 3 or 4 occurred more frequently in those receiving combination therapy, although this was not statistically significant. The data confirm the unmet need for better treatment in R/R PTCL. Despite a small sample, the analysis shows greater response and survival in those treated with single agents as first retreatment in R/R setting, while maintaining the ability to achieve transplantation. Large, randomized trials are needed to identify the best strategy., (© 2019 Wiley Periodicals, Inc.)

Background: Patients with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy are at increased risk of developing therapy-related (t-) myelodysplastic syndrome (MDS). It is unclear whether antecedent CLL adds prognostic value to the revised International Prognostic Scoring System (IPSS-R) for MDS. We performed a retrospective analysis to evaluate the significance of a previous CLL diagnosis as an independent adverse prognostic factor., Patients and Methods: We identified 18 consecutive patients with t-MDS, previously treated for CLL (CLL-MDS) from 2002 to 2016. For each CLL-MDS patient, we identified 2 control patients with de novo MDS matched for age (≤ 65 or > 65 years), IPSS-R (≤ 3 or > 3), and year of MDS diagnosis (before or after 2008). Multivariable models were developed to test for independent predictors of progression to acute myeloid leukemia (AML) and overall survival (OS)., Results: Median time from CLL to MDS diagnosis was 58.8 months (range, 12-280 months) and median number of treatment lines for CLL was 1 (range, 1-5), including alkylating agents in 15 patients (83%) and fludarabine, cyclophosphamide, rituximab in 12 patients (67%). Hypomethylating agents were administered in 13 (72%) of CLL-MDS patients and 33 (91%) of de novo MDS patients. After a median follow-up of 19.2 months, OS was not different between CLL-MDS and matched de novo MDS patients. CLL-MDS patients with IPSS-R score ≤ 3 had better OS compared with those with IPSS-R score > 3. In multivariate analysis, there was no significant independent association between history of CLL OS or progression to AML., Conclusion: History of CLL did not independently affect OS in t-MDS patients beyond IPSS-R score., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1., Methods: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis., Results: Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89)., Conclusions: This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL., (© 2019 American Cancer Society.)

Purpose: The aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL)., Patients and Methods: Adult patients with relapsed/refractory PTCL-one or more prior therapy-were randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m 2 (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m 2 or intravenous romidepsin 14 mg/m 2 (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned., Results: Between May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm., Conclusion: In patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm.

We sought to develop a safe and effective outpatient salvage regimen by replacing ifosfamide within the (R)ICE (rituximab, ifosfomide, carboplatin, etoposide) regimen with bendamustine (T(R)EC) via a multicentre phase I/II study for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). Therapy consisted of 60-120 mg/m 2 per day bendamustine on days 1 and 2 in combination with carboplatin, etoposide and rituximab (only for CD20 + lymphoma) used in the (R)ICE regimen for up to 2 cycles. The objectives were to define a maximally tolerated dose (MTD) of bendamustine, determine safety and toxicity, assess efficacy, and evaluate impact on stem cell collection. Forty-eight patients were treated of which 71% had refractory disease. No dose-limiting toxicities were observed. The recommended phase II dose of bendamustine was 120 mg/m 2 per day on days 1 and 2. Response rates were 85% (70% complete response, CR) in HL, and 65% (40% CR) in DLBCL. Stem cell collection was successful in 30 of 32 patients. The most common non-haematological toxicities ≥grade 3 were febrile neutropenia (8%) and dehydration (8%). The T(R)EC regimen safely yields high response rates, successfully mobilizes peripheral blood stem cells and compares favourably to RICE, offering an effective outpatient treatment option for patients with relapsed or refractory DLBCL and HL., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

HyperCVAD is a commonly-used regimen for adults with newly-diagnosed acute lymphoblastic leukemia (ALL). However, relatively little is known about the application of minimal residual disease (MRD) detection with this treatment. To address this, we studied 142 adults with ALL treated with hyperCVAD over a 10-year period who had MRD assessed by either multi-parameter flow cytometry or (for patients with Philadelphia chromosome positive ALL) reverse transcriptase polymerase chain reaction for the BCR-ABL1 translocation. In a multivariate analysis, patients who achieved MRD negativity (MRD Neg ) at any point had significantly better overall survival (OS; hazard ratio [HR] 0.43; P = .01) and event-free survival (EFS; HR 0.27; P < .01). Of 121 patients with MRD assessed at various points within 90 days of starting hyperCVAD, 50% (n = 61) had achieved MRD Neg . Among those that became MRD Neg , the median time to MRD Neg was 68 days. Time to MRD Neg was significantly associated with EFS (P = .009), but not OS (P = .19), implying increasingly better EFS the earlier MRD Neg is achieved. These data add to our understanding of MRD assessment during treatment with hyperCVAD, aide clinicians with predicting relapse risk, and provide additional historical data on which future clinical trials can be designed., (© 2018 Wiley Periodicals, Inc.)

This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively ( P <0.001). Patients receiving or not salvage bone marrow transplantation had a 3-year survival of 48% and 18%, respectively ( P <0.001). In a univariate Cox regression analysis, refractory disease was associated with a higher risk of death (HR=1.43, P =0.001), whereas late relapse (>12 months, HR 0.57, P =0.001) and salvage therapy with transplantation (HR=0.36, P <0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation., (Copyright© 2018 Ferrata Storti Foundation.)

This phase 1 study evaluated frontline brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab vedotin monotherapy) in 26 patients with CD30 + peripheral T-cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5-year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789., (© 2018 by The American Society of Hematology.)

This phase 2 study evaluated brentuximab vedotin monotherapy in CD30-expressing DLBCL; after several patients with little to no CD30 achieved a complete remission (CR), the study evaluated treatment of DLBCL with undetectable CD30 (CD30u) by local visual immunohistochemistry (vIHC). Sixteen of 52 CD30u DLBCL patients (31%) had an objective response (6 CRs [12%]). Median progression-free survival (PFS) was 1.4 months (range, 0.4-15.6) and median overall survival (OS) was 7.5 months (range, 0.7-18.6+). Subsequent CD30 expression quantitated by computer-assisted digital image analysis (cIHC) showed that 11 of 16 CD30u DLBCL responders had ≥1% CD30. Correlative analyses of CD30u and CD30-expressing DLBCL combined demonstrated that ≥1% CD30 expression by cIHC resulted in a trend toward a higher response rate and significantly longer median PFS and OS. A minimum CD30 expression threshold appears to be required for antitumor activity in DLBCL; however, other factors also likely contribute to activity. (NCT01421667).

Background: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study., Patients and Methods: We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression., Results: The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia)., Conclusions: Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response., Clinical Trial Registration: ClinicalTrials.gov # NCT01393106., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. PATIENTS AND METHODS: We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States., Results: A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P = .01)., Conclusion: The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organization classification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States., Methods: Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided., Results: Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09])., Conclusions: To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174-1183. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Peripheral T-cell lymphoma and natural killer/T-cell lymphomas (PT/NKCL) make up a diverse subgroup of non-Hodgkin's lymphomas characterized by an aggressive clinical course. The use of hematopoietic stem cell transplantation (HSCT) in the treatment of PT/NKCL remains controversial because of the absence of randomized controlled trials. The best available data suggest that certain subtypes of PT/NKCL may benefit more from the application of HSCT than other subtypes and that this benefit results from their unique clinical characteristics and underlying biology. Ultimately, however, prospective randomized controlled trials are needed to clarify the optimal type and timing of HSCT in patients with PT/NKCL., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Independent central review of clinical imaging remains the standard for oncology clinical trials with registration potential. A limited independent central review strategy has been proposed for solid tumor trials based on concordance between central and local evaluation of response. Concordance between independent central review and local evaluation of response in hematological malignancies is not known., Methods: We retrospectively evaluated concordance between prospectively performed central and local assessments of response using the Revised Response Criteria for Malignant Lymphoma across two international, open-label, single-arm, registration studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma (N = 102) or systemic anaplastic large-cell lymphoma (N = 58)., Results: Overall objective response rates were similar between assessors for both the trial in Hodgkin lymphoma (75% independent central review, 72% local evaluation) and the trial in anaplastic large-cell lymphoma (86% independent central review, 83% local evaluation). Patient-specific objective response concordance was also substantial (Hodgkin lymphoma: kappa = 0.68; anaplastic large-cell lymphoma: kappa = 0.74). Median progression-free survival was similar between assessors for patients with anaplastic large-cell lymphoma (14.3 months by independent central review (95% confidence interval: 6.9, -); 14.5 months by local evaluation (95% confidence interval: 9.4, -)), but longer by local evaluation in patients with Hodgkin lymphoma (5.8 months by independent central review (95% confidence interval: 5.0, 9.0); 9.0 months by local evaluation (95% confidence interval: 7.1, 12.0)). Median duration of response was longer by local evaluation in both malignancies, which was primarily attributable to earlier computed tomography and positron emission tomography-based scoring of progression by independent central review., Conclusion: A limited independent review audit strategy for clinical trials of some lymphomas appears feasible and practical based on substantial concordance in assessments of overall objective response by central and local evaluation in two international, prospective, registration trials in lymphoma. Some variability between assessors in the time-to-event endpoints was observed, which appeared attributable to earlier assignments of progression by independent central review compared with local evaluation., (© The Author(s) 2016.)

Comparisons without hematopoietic cell transplantation (HCT) to myeloablative (MAC) or reduced-intensity HCT (RIC) for adults with acute lymphoblastic leukemia (ALL) in first minimal-residual-disease negative remission (MRD(Neg) CR1) are limited. Further, the importance of MRD(Neg) following salvage therapy (MRD(Neg) CR2+) is unknown. We evaluated 89 patients in MRD(Neg) CR1 after adult-inspired treatment: 33 received MAC (12 Philadelphia chromosome [Ph]+), 17 received RIC (13 Ph+), and 39 Deferred HCT (3 Ph+). Three-year overall survival (OS) estimates for MAC, RIC, and Deferred HCT were 71%, 69%, and 68%, while 3-year event-free survival (EFS) estimates were 65%, 54%, and 28%, respectively. Further, HCT in MRD(Neg) CR1 performed similarly to MRD(Neg) CR2+: 3-year OS estimates were 70% and 69%, and 3-year EFS estimates were 62% and 62%, respectively. In conclusion, adults with ALL in MRD(Neg) CR1 following adult-inspired therapy had similar OS with or without HCT, and HCT in MRD(Neg) CR2 + can yield long-term survival., Competing Interests: Statement RDC: Research Support: Pfizer, Seattle Genetics. ARS: Research Support: Pfizer. The remaining authors declare no relevant financial conflicts of interest.

Purpose: To compare incidence and survival of peripheral T-cell lymphoma (PTCL) subtypes among US racial/ethnic groups., Methods: Patients with PTCL (age ≥ 15 years; 2000 to 2012) were identified in the Surveillance, Epidemiology, and End Results (SEER) registries. Race/ethnicity was categorized as non-Hispanic white, black, Asian/Pacific Islander, Hispanic white, or American Indian/Alaskan native. Age-standardized annual incidence rates and incidence rate ratios were estimated with 95% CIs, and case-case odds ratios were estimated by race/ethnicity using polytomous regression. Survival was estimated from SEER follow-up data with Cox regression., Results: Thirteen thousand one hundred seven patients with PTCL were identified. Annual PTCL incidence was highest in blacks and lowest in Native Americans. Compared with non-Hispanic whites, blacks had a higher incidence of PTCL not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma, and adult T-cell leukemia/lymphoma (ATLL) and a lower incidence of angioimmunoblastic T-cell lymphoma (AITL); Asians/Pacific Islanders had a higher incidence of AITL, extranodal nasal-type natural killer/T-cell lymphoma and NK-cell leukemia (ENKCL), and ATLL and a lower incidence of anaplastic large-cell lymphoma; Hispanics had a higher incidence of AITL and ENKCL; and Native Americans had a lower incidence of PTCL-NOS (all P < .05). The ratio of ENKCL to PCTL-NOS among Native Americans, Asians/Pacific Islanders, and Hispanic whites was approximately three- to four-fold the same ratio among non-Hispanic whites. Survival varied significantly by race/ethnicity (P < .001), with blacks in particular experiencing shorter survival for most subtypes., Conclusion: Striking variation in incidence, proportions of PTCL subtypes, and survival was observed. Aspects of these PTCL subtype patterns, such as for ENKCL and ATLL, were similar to corresponding global populations. Despite the small population size and limited number of Native American patients, PTCL subtype frequencies in this group were distinct but most similar to Hispanic whites. Survival disparities were evident, especially for blacks compared with non-Hispanic whites., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2016 by American Society of Clinical Oncology.)

Purpose: To assess the safety and efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)., Experimental Design: Relapsed or refractory DLBCL patients originally received the oral spleen tyrosine kinase inhibitor, fostamatinib in a two-arm, randomised, double-blinded manner at either 100 mg twice a day (BID) or 200 mg BID until disease progression or unacceptable toxicity. The primary objective was to assess the overall response rate (ORR). Preliminary analysis showed limited efficacy and all subsequent patients were treated at 200 mg BID. Previously randomised patients were unblinded and given the opportunity to receive 200 mg BID., Results: Sixty-eight patients were treated (47 at 200 mg BID, 21 at 100 mg BID). Cell of origin analysis showed 58% germinal B-cell (GCB) origin, 30% activated B-cell (ABC) origin and 12% with an intermediate cell of origin signature. The most common treatment-related adverse events of all patients were diarrhoea (21% total, 6% grade 3/4), nausea (19% total, 3% grade 3/4), and, fatigue (18% total, 9% grade 3/4). The ORR rate was 3% across both arms and clinical benefit (≥ stable disease) was achieved for 13% of all patients. The cell of origin for patients with clinical benefit was GCB (4 patients), intermediate (4 patients) or unknown (1 patient). None of the patients with clinical benefit had ABC genotype., Conclusions: While fostamatinib was generally well tolerated in this patient population, efficacy at these doses and schedule was poor. Unlike data with other B-cell antigen receptor pathway inhibitors, responses were not observed in the ABC genotype., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survival, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21·5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need., (© 2015 John Wiley & Sons Ltd.)

Autologous stem cell transplantation (ASCT) is standard therapy for mantle cell lymphoma (MCL) in remission after induction chemotherapy, with the best results for patients in complete remission (CR). We hypothesized that evaluation of minimal residual disease (MRD) before ASCT could further stratify outcomes for these patients. Patients with MCL who underwent ASCT in clinical CR between 1996 and 2011 with pretransplantation MRD testing were eligible. Presence of a clonal IgH rearrangement, t(11; 14) by PCR or positive flow cytometry from blood or bone marrow, was considered positive. An adjusted proportional hazards model for associations with progression-free (PFS) and overall survival (OS) was performed. Of 75 MCL patients in CR, 8 (11%) were MRD positive. MRD positivity was associated with shorter OS and PFS. The median OS for MRD-negative patients was not reached, with 82% survival at 5 years, whereas for the MRD-positive patients, median OS was 3.01 years (hazard ratio [HR], 4.04; P = .009), with a median follow-up of 5.1 years. The median PFS for MRD-negative patients was not reached with 75% PFS at 5 years, whereas for MRD-positive patients, it was 2.38 years (HR, 3.69; P = .002). MRD positivity is independently associated with poor outcomes after ASCT for MCL patients in CR., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Despite initial responses to chemoimmunotherapy, relapse and minimal residual disease (MRD) remain major issues in treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients. We administered (131)I-tositumomab to patients in complete response (CR) or partial response (PR) after induction chemotherapy. Toxicities and rate of PR to CR conversion and MRD elimination were assessed three months later. The study stopped prematurely after enrolling 16 patients. Four (25%) were in CR, 12 (75%) in PR, and 12 (75%) had MRD. Three months after treatment with (131)I-tositumomab, CR was achieved (n = 8; 50%) or sustained (n = 4; 25%) in 12 patients and MRD was eliminated in four of 12 patients (33%). Hematologic toxicities were anemia in one patient (6%), neutropenia in 13 (81%), and thrombocytopenia in eight (50%). Two patients (12%) developed MDS 17 and 20 months after consolidation. Consolidation with (131)I-tositumomab for CLL/SLL patients in first remission is feasible and may provide the benefit of converting PR to CR and/or eliminating MRD.

Autologous stem cell transplant (ASCT) can improve outcomes for mantle cell lymphoma (MCL) patients, yet relapses are frequent. We hypothesized that high-dose anti-CD20 radioimmunotherapy (RIT)-based conditioning could improve results in this setting. We thus assessed 162 consecutive patients with MCL at our centre undergoing ASCT following high-dose RIT-based (n = 61) or standard (n = 101) conditioning. RIT patients were less likely to be in first remission (48% vs. 72%; P = 0·002), be in complete remission (CR) (26% vs. 61%; P < 0·001) and have chemosensitive disease (84% vs. 96%; P = 0·006). RIT-based conditioning was associated with a reduced risk of treatment failure [hazard ratio (HR) 0·40; P = 0·001] and mortality (HR 0·49; P = 0·01) after adjusting for these imbalances. This difference increased as disease status worsened (from CR to partial remission to stable/progressive disease), with respective HRs of 1·14, 0·53 and 0·04 for mortality, and 0·66, 0·36 and 0·14 for treatment failure. RIT-based conditioning appears to improve outcome following ASCT for MCL patients unable to achieve CR after controlling for imbalances in important risk factors. These data support the further study of RIT and radiation-based strategies in a risk-adapted approach to ASCT for persistent MCL., (© 2015 John Wiley & Sons Ltd.)

Normalization of fluorodeoxyglucose positron emission tomography (FDG PET) imaging prior to high-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes in relapsed and refractory (RR) Hodgkin lymphoma (HL), but many patients refractory to platinum-based salvage regimens are unable to achieve this goal. We therefore investigated whether brentuximab vedotin (BV) could normalize FDG PET in platinum-refractory HL prior to ASCT. Fifteen consecutive patients with RR HL and FDG PET positive disease after platinum-based salvage therapy were treated with a median of 4 cycles of BV. Normalization of FDG PET (Deauville ≤2) occurred in 8/15 (53%) patients but was only observed in patients that had achieved partial remission or stable disease after platinum-based salvage therapy. All patients eventually proceeded to ASCT, regardless of FDG PET status. Our data suggest that BV can normalize FDG PET in a subset of patients with platinum-refractory HL prior to ASCT., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined., Patients and Methods: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation., Results: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed., Conclusions: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Brentuximab vedotin is an antibody drug conjugate that induces durable objective responses in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Fifteen of 160 patients who participated in two pivotal phase 2 studies received a consolidative allogeneic stem cell transplant (allo-SCT) following brentuximab vedotin treatment. This case series describes their experience. The studies were approved by Institutional Review Boards prior to patient enrollment. Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks for up to 16 cycles. The estimated 2-year progression-free survival (PFS) rate was 66%, and the median PFS has not yet been reached. Eleven of the 15 patients were alive and the estimated 2-year survival rate was 80%. The safety of brentuximab vedotin treatment in this series was consistent with the known safety profile in this setting. Brentuximab vedotin is a compelling option for reducing tumor burden to facilitate a consolidative allo-SCT.

Patients with rituximab-refractory follicular lymphoma (FL) have limited options. Before the rituximab era, autologous stem cell transplant (ASCT) was shown to improve outcomes in chemotherapy-sensitive, relapsed FL, but the impact of rituximab-sensitivity on these results is unknown. We analyzed 194 consecutive relapsed patients with FL who underwent ASCT at out center and categorized them as rituximab-sensitive (RS, n = 35), rituximab-refractory (RR, n = 65) or no rituximab (NoR, n = 94) if transplanted before rituximab was used. Progression-free survival at 3 years was 85% in RS and 35% in RR patients (p = 0.0004). Only rituximab-sensitivity was significant on multivariate analysis with improved overall survival (OS) (hazard ratio [HR] 0.24, p = 0.01) and progression-free survival (PFS) (HR 0.35, p = 0.006) in RS patients and increased relapse in RR patients (HR 2.11, p = 0.01). Pre-transplant rituximab-sensitivity is a strong independent predictor of post-transplant outcomes in relapsed FL, although one-third of RR patients achieved a PFS of over 3 years with ASCT.

Purpose: Front-line treatment of peripheral T-cell lymphomas (PTCL) involves regimens such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and results in a 5-year overall survival (OS) rate of less than 50%. This phase I open-label study evaluated the safety and activity of brentuximab vedotin administered sequentially with CHOP or in combination with CHP (CHOP without vincristine) as front-line treatment in patients with CD30(+) PTCL., Patients and Methods: Patients received sequential treatment (once every 3 weeks) with brentuximab vedotin 1.8 mg/kg (two cycles) followed by CHOP (six cycles) or brentuximab vedotin 1.8 mg/kg plus CHP (BV+CHP) for six cycles (once every 3 weeks). Responders received single-agent brentuximab vedotin for eight to 10 additional cycles (for a total of 16 cycles). The primary objective was assessment of safety; secondary end points included objective response rate, complete remission (CR) rate, progression-free survival rate (PFS), and OS. There were no prespecified comparisons of the two treatment approaches., Results: After sequential treatment, 11 (85%) of 13 patients achieved an objective response (CR rate, 62%; estimated 1-year PFS rate, 77%). Grade 3/4 adverse events occurred in eight (62%) of 13 patients. At the end of combination treatment, all patients (n = 26) achieved an objective response (CR rate, 88%; estimated 1-year PFS rate, 71%). All seven patients without anaplastic large-cell lymphoma achieved CR. Grade 3/4 adverse events (≥ 10%) in the combination-treatment group were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%)., Conclusion: Brentuximab vedotin, administered sequentially with CHOP or in combination with CHP, had a manageable safety profile and exhibited substantial antitumor activity in newly diagnosed patients with CD30(+) PTCL. A randomized phase III trial is under way, comparing BV+CHP with CHOP (clinical trial No. NCT01777152)., (© 2014 by American Society of Clinical Oncology.)

Older adults constitute a significant proportion of the cancer population, but are underrepresented in clinical trials. We conducted a retrospective analysis of the safety and efficacy of brentuximab vedotin in adults ≥ 60 years with relapsed CD30-positive lymphomas. Baseline characteristics and safety data were compared for older (median age 66) and younger patients (< 60 years, median age 32). Exposure to brentuximab vedotin was comparable. Older patients had more preexisting conditions (median 11 vs. 6) and were receiving more concomitant medications (median 7.5 vs. 4). Higher rates of anemia (30% vs. 10%), peripheral sensory neuropathy (60% vs. 46%), fatigue (58% vs. 43%) and adverse events ≥ grade 3 (70% vs. 56%) occurred in older patients. Objective response rates were 56% and 100% in older patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively. With appropriate monitoring, brentuximab vedotin may represent a meaningful clinical option for older patients with relapsed CD30-positive lymphomas.

Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2·5 μmol/l concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 d in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty-nine patients [median age 56 years, median 2 prior therapies, 14 chemoresistant (of 27 evaluable), 2 prior transplants] were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 d. Common dose limiting toxicities included infection (n = 2), hypokalaemia (n = 2), and transaminitis (n = 2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4·5 μmol/l (range 4·2-6·0 μmol/l) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted., (© 2013 Blackwell Publishing Ltd.)

Systemic treatment for cutaneous T-cell lymphoma (CTCL) involves the use of less aggressive, well-tolerated therapies. Pralatrexate is a novel antifolate with high affinity for reduced folate carrier-1. A dose de-escalation strategy identified recommended pralatrexate dosing for patients with CTCL that demonstrated high activity, good rates of disease control, and an acceptable toxicity profile for continuous long-term dosing. Eligibility included mycosis fungoides, Sézary syndrome, or primary cutaneous anaplastic large cell lymphoma, with disease progression after ≥ 1 prior systemic therapy. The starting dose and schedule was 30 mg/m(2)/wk intravenously for 3 of 4 (3/4) weeks. Subsequent starting doses were 20, 15, and 10 mg/m(2)/wk for 3/4 or 2 of 3 (2/3) weeks. Response was evaluated by the modified severity-weighted adjustment tool. Fifty-four patients were treated. The recommended regimen was identified as 15 mg/m(2)/wk for 3/4 weeks and was explored in the expansion cohort. In 29 patients treated overall with the recommended dosing regimen, the median number of prior systemic therapies was 4. Pralatrexate was administered for a median of 4 cycles; response rate was 45%. The most common grade 3 adverse event (AE) was mucositis (17%); the only grade 4 AE was leukopenia (3%). Pralatrexate 15 mg/m(2)/wk for 3/4 weeks shows high activity with acceptable toxicity in patients with relapsed/refractory CTCL.

Reduced-intensity conditioning (RIC) before allogeneic hematopoietic cell transplantation (HCT) is increasingly used as a potentially curative option for patients with advanced lymphoma; however, relapse remains a major challenge. Unfortunately, little data are available on outcomes, predictors of survival, and results of specific management strategies in these patients. In the present study, a total of 101 consecutive relapses occurred and were evaluated in 280 patients with lymphoma who underwent RIC HCT. Diseases included aggressive non-Hodgkin lymphoma (NHL) (n = 42), indolent NHL (n = 33), and Hodgkin lymphoma (HL) (n = 26). Median time to relapse was 90 days (range, 3-1275 days), and graft-versus-host disease at relapse was present in 56 patients (55%). Interventions after relapse included no therapy (n = 14), withdrawal of immunosuppression alone (n = 11), chemoradiotherapy (n = 60), and donor lymphocyte infusion/second HCT (n = 16). Overall survival (OS) was 33% (95% confidence interval [CI], 23%-44%) at 3 years after relapse and 23% (95% CI, 13%-34%) at 5 years after relapse. Both aggressive NHL (vs indolent disease; hazard ratio, 2.29; P = .008) and relapse within 1 month post-HCT (vs >6 months; hazard ratio, 3.17; P = .004) were associated with increased mortality. Estimated 3-year OS was 16% (95% CI, 5%-32%) after relapse for aggressive NHL, 40% (95% CI, 19%-61%) after relapse for indolent NHL, and 47% (95% CI, 29%-64%) after relapse for HL. The 1-year survival was 24% for patients relapsing within 1 month post-HCT, compared with 52% for those relapsing at 1-3 months, 74% for those relapsing at 3-6 months, and 77% for those relapsing at more than 6 months. We conclude that despite relapse of lymphoma after RIC HCT, some patients may experience prolonged survival, with better postrelapse outcomes occurring in patients with indolent NHL, HL, or late relapse., (Copyright © 2011 American Society for Blood Marrow Transplantation. Published by Elsevier Inc. All right resecved. Published by Elsevier Inc. All rights reserved.)

This phase I/II study was conducted to determine the maximum tolerated dose, toxicity, and efficacy of clofarabine in combination with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming (GCLAC), in the treatment of patients with relapsed or refractory acute myeloid leukaemia (AML). Dose escalation of clofarabine occurred without dose-limiting toxicity, so most patients were treated at the maximum dose, 25 mg/m(2) per day with cytarabine 2 g/m(2) per day, each for 5 d, and G-CSF 5 μg/kg, beginning the day before chemotherapy and continuing daily until neutrophil recovery. The complete remission (CR) rate among the 46 evaluable patients was 46% (95% confidence interval [CI] 31-61%) and the CR + CR but with a platelet count <100 × 10(9)/l rate was 61% (95% CI 45-75%). Multivariate analysis showed that responses to GCLAC were independent of age, cytogenetic risk category, and number of prior salvage regimens. GCLAC is highly active in relapsed and refractory AML and warrants prospective comparison to other regimens, as well as study in untreated patients., (© 2011 Blackwell Publishing Ltd.)

Purpose: High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) are frequently used in an attempt to improve outcome in patients with mantle-cell lymphoma (MCL); however, the importance of intensive induction regimens before transplantation is unknown., Patients and Methods: To address this question, we evaluated baseline characteristics, time to treatment, induction regimen, disease status at the time of transplantation, and MIPI score at diagnosis and their associations with survival in 118 consecutive patients with MCL who received HDT and ASCT at our centers., Results: The MIPI was independently associated with survival after transplantation in all 118 patients (hazard ratio [HR], 3.5; P < .001) and in the 85 patients who underwent ASCT as initial consolidation (HR, 7.2; P < .001). Overall survival rates were 93%, 60%, and 32% at 2.5 years from ASCT for all patients with low-, intermediate-, and high-risk MIPI, respectively. Low-risk MIPI scores were more common in the intensive induction group than the standard induction group in all patients (64% v 46%, respectively; P = .03) and in the initial consolidation group (66% v 45%, respectively; P = .03). After adjustment for the MIPI, an intensive induction regimen was not associated with improved survival after transplantation in all patients (HR, 0.5; P = .10), the initial consolidation group (HR, 1.1; P = .86), or patients ≤ 60 years old (HR, 0.6; P = .50). Observation of more than 3 months before initiating therapy did not yield inferior survival (HR, 2.1; P = .12) after adjustment for the MIPI in patients receiving ASCT., Conclusion: An intensive induction regimen before HDT and ASCT was not associated with improved survival after adjusting for differences in MIPI scores at diagnosis.

Purpose: Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of pralatrexate, a novel antifolate with promising activity., Patients and Methods: Patients with independently confirmed PTCL who progressed following ≥ 1 line of prior therapy received pralatrexate intravenously at 30 mg/m(2)/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS)., Results: Of 115 patients enrolled, 111 were treated with pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%)., Conclusion: To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease.