Untreated Peripheral T-cell Lymphomas Research Articles

Upfront Allogeneic-Stem Cell Transplantation for Patients with Non-Localized Untreated Peripheral T-Cell Lymphoma: An Intention-to-Treat Analysis from a Single Center

Background. Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases with dismal outcome when treated with chemotherapy alone. Because allogeneic stem cell transplantation (allo-SCT) can cure relapse-refractory patients, we hypothesised that upfront allo-SCT may be less toxic and provide a better outcome. Therefore, all patients that presented with advanced PTCL in our institution at diagnosis were scheduled to undergo upfront allo-SCT after induction chemotherapy.Patients and methods. The aim of the present work was to assess the feasibility and toxicity of upfront allo-SCT. From 2004 to 2012, 49 newly diagnosed PTCL patients were scheduled to receive upfront allo-SCT. An HLA-matched donor was found for 42 patients: related to the patient in 15 cases, unrelated in 20 cases, and suitable cord blood units were used in seven cases.Results. After induction chemotherapy, 17 patients reached complete remission and 29 (60%) proceeded to upfront allo-SCT. For all patients, the one and two-year overall survival (OS) rates were 59% (CI95%; 47-75) and 55 % (CI95%; 43-71), respectively. The most frequent reason we did not proceed to allo-SCT was disease progression or insufficient response after induction. For transplanted patients, the one- and two-year OS were 76% (CI95%; 62-93) and 72.5% (CI95%; 58-91), respectively. Toxicity related mortality one year after allo-SCT was only 8.2% (CI95%; 0-18.5). The two-year progression-free survival (PFS) rate of patients who did not proceed to allo-SCT (n= 20) was below 30%. The disease status at the time of transplantation was a strong predictive marker for both PFS and OS in transplant patients.Conclusions. Upfront allo-SCT in PTCLs is feasible with low TRM, and it provides long-term disease control. However one third of patients remain chemo-refractory, and thus, new therapeutic approaches are warranted. The role of upfront allo-SCT compared to other therapeutic approaches in PTCLs requires investigation in randomized studies. DisclosuresNo relevant conflicts of interest to declare.

ROCHOP study: A phase III randomized study of CHOP compared to romidepsin-CHOP in untreated peripheral T-cell lymphoma.

TPS8616 Background: Peripheral T-cell lymphomas (PTCL) account for 10-15% of lymphomas. They share an aggressive clinical behaviour and a poor prognosis when treated by CHOP-like regimen which is nevertheless consider as a standard because others regimens failed to demonstrate survival advantage. Romidepsin is a histone deacetylase inhibitor with promising results in PTCL. First trials showed a response rate of 38% in heavily pre-treated PTCL patients. These results were confirmed with 15% of patients reaching a CR/CRu, 89% of them without disease progression at 13 months. Adverse events include gastrointestinal, hematologic and asthenic conditions. A phase I study of romidepsin combined with CHOP was conducted by LYSA. A total of 18 patients were included. The recommended dose was 12 mg/m² administered at day 1 and day 8 of each cycle. Methods: Ro-CHOP study is an international phase III study comparing 6 cycles of CHOP21 with 6 cycles of romidepsin-CHOP21 (EUDRACT 2012-001580-68). Primary endpoint is Progression-Free Survival assessed independently. Secondary objectives include overall survival, other efficacy parameters, analysis of response rate according to 18FDG-PET, safety, quality of life and biological ancillary studies. A total of 420 subjects aged from 18 to 80 years will be enrolled in the study. Main inclusion criteria are untreated PTCL whatever Ann Arbor stage and a performance status of 0-2. Main exclusion criteria are other subtypes of lymphoma, HTLV1 positivity, any cardiac abnormality, poor renal, hepatic and marrow functions unless related to lymphoma. Patients are randomized 1:1 between the two regimens. A stratification is performed with IPI score, age and histology. The first patient has been included in January 2013. A recruitment of 10.5 patients per month is anticipated, with a total duration of the study of 60 months. An update on enrolment will be presented at the meeting. Clinical trial information: 2012-001580-68.

Phase I study of vorinostat in combination with standard CHOP in patients with newly diagnosed peripheral T‐cell lymphoma

Phase I study of vorinostat in combination with standard <scp>CHOP</scp> in patients with newly diagnosed peripheral T‐cell lymphoma

A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study

This phase II study to determine the safety and efficacy of denileukin diftitox (DD) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) enrolled patients with newly diagnosed peripheral T-cell lymphoma (PTCL). Forty-nine received DD 18 μg/kg/day (days 1, 2) with CHOP (day 3) every 21 days for ≤ 6–8 cycles. Intent-to-treat (ITT) and safety populations comprised all patients. In the ITT population, the overall response rate was 65%, median duration of response was 30 months and median progression-free survival was 12 months. Median overall survival was not attained at the end of the study, and the overall survival rate was 63.3%. The two most frequent treatment-related adverse events (AEs) were fatigue and nausea. Most frequent AEs ≥ grade 3 within the hematologic system were lymphopenia (24.5%), neutropenia (20.4%) and leukopenia (18.4%). Three treatment-related deaths occurred. DD plus CHOP was well tolerated, and progression-free and overall survival improved versus historical comparison with CHOP alone. Confirmation in larger trials is warranted.

A Phase Ib Trial of Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma (PTCL): The Ro-CHOP Study

AbstractAbstract 1617 Background:Romidepsin is a selective class 1 histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 phase II studies with overall response rates of 25–38% (Piekarz, Blood 2011;117:5827; Coiffier, J Clin Oncol 2012;30:631). Toxicity was mainly hematologic and digestive. The aim of the present study was to evaluate the safety, tolerability and efficacy of different doses of romidepsin in association with CHOP in patients with previously untreated PTCL. Methods:Patients with biopsy-proven PTCL were planned to receive 8 cycles of CHOP (cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1 – 5) in association with varying doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 on days 1 & 8 was chosen. The dose-variation scheme follows a traditional “3+3” design. Dose-limiting toxicity (DLT) were considered during the first 2 cycles. Results:Eighteen patients (11 male, 7 female, aged 31 to 78) have been included and are analyzable for toxicity during the first two cycles. Diagnoses were: PTCL, not otherwise specified (n=10), angioimmunoblastic TCL (n=4), other PTCL (n=4). ECOG performance status was good (0–1) in all but one patient; 17/18 had stage III-IV disease; LDH levels were elevated in 11/18. The age-adjusted IPI score was 0 (n=1), 1 (n=14), 2 (n=3). Significant, albeit tolerable haematological toxicity having been observed in the first two cohorts, the definition of DLT was modified during the course of the study. The study diagram is shown in the figure. Accrual of the phase Ib part of the study is now completed and the phase II part is ongoing with a dose of 12 mg/m2 D1&8. Serious adverse events of interest included: One episode of acute pulmonary edema after course 1 in 1 patient, acute coronary syndrome (n=1), deep venous thrombosis (n=1) and cardiac arrhythmia (n=1). Among 14 evaluable patients, 3 progressed during treatment or shortly after end of treatment; and 11 responded (partial response 3/14, complete response 8/14) for an overall response rate of 78%. The 4 other patients have not yet reached the 8 cycles. Conclusion:Romidepsin can be combined with CHOP at the price of foreseeable hematological toxicity. Some cardiovascular events have been observed but the relationship with romidepsin is questionable. The dose of 12 mg/m2 on days 1& 8 is currently evaluated in the phase 2 part of the study. Response rates seem promising, but longer follow-up is needed. Updated results will be presented at the meeting. [Display omitted] Disclosures:Ribrag:Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding. Coiffier:Celgene: Consultancy.

Up-Front Autologous Stem-Cell Transplantation in Peripheral T-Cell Lymphoma: NLG-T-01

Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large prospective phase II study in untreated systemic PTCL. This is the final report, with a 5-year median follow-up, of the NLG-T-01 study. Treatment-naive patients with PTCL age 18 to 67 years (median, 57 years) were included. Anaplastic lymphoma kinase (ALK) -positive anaplastic large-cell lymphoma (ALCL) was excluded. An induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) was administered (in patients age > 60 years, etoposide was omitted). If in complete or partial remission, patients proceeded to consolidation with HDT/ASCT. Of 166 enrolled patients, 160 had histopathologically confirmed PTCL. The majority presented with advanced-stage disease, B symptoms, and elevated serum lactate dehydrogenase. A total of 115 underwent HDT/ASCT, with 90 in complete remission at 3 months post-transplantation. Early failures occurred in 26%. Treatment-related mortality was 4%. At 60.5 months of median follow-up, 83 patients were alive. Consolidated 5-year overall and progression-free survival (PFS) were 51% (95% CI, 43% to 59%) and 44% (95% CI, 36% to 52%), respectively. Best results were obtained in ALK-negative ALCL. Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL.

Efficacy of alemtuzumab (ALZ) in combination with dose-adjusted EPOCH (DA-EPOCH) in untreated nodal peripheral T-cell lymphoma (PTCL).

8051 Background: The survival of patients (pts) with PTCL (excluding ALCL) is disappointing following anthracycline-based therapy and novel approaches are needed. In diffuse large B-cell lymphoma, the addition of anti-CD20 therapy to CHOP has significantly improved outcome and we investigated if in PTCL, adding ALZ – which targets CD52, expressed on most PTCLs – was feasible and improved outcome. Methods: This was a single-center phase I/II trial of ALZ, in combination with DA-EPOCH in patients with treatment-naïve CD52+ PTCL. The MTD of 30 mg ALZ was combined with DA-EPOCH for phase II evaluation resulting in an intention-to-treat population (ITTP) of 30 pts. Results: Patient (n=30) characteristics: median (range) age 50 (17-77); M:F 1:1; Stage III/IV 27 (90%); IPI ≥2 22 (73%). Histologies: ATLL 11 (37%), PTCL NOS 6 (20%), AITL 5 (16%), Hepatosplenic 3 (10%), Peripheral T NK cell 2 (7%), Other 3 (10%). At 67 months median follow-up, 11 patients were alive, 10 disease-free. Median overall (OS) and event-free survivals (EFS) were 15.4 and 6.7 months respectively. Outcome was substantially better for pts with ‘nodal’ (AITL, PTCL-NOS, Other) compared to ‘non-nodal’ (ATLL and ‘extranodal’ histologies) PTCL subtypes. 3-year OS for the two groups was 58.3% and 27.8% respectively (p=0.082); 3-yrs EFS was 50% (median 27.0 months) and 22.2% (median: 5 months) respectively (p=0.041). Half of the ‘nodal’ PTCL pts had sustained long-term complete remissions demonstrated by a plateau in the EFS curve at 27 months. There were 3 treatment related deaths: 2 from neutropenic sepsis; 1 from toxoplasma. Other toxicities included CMV and BK virus reactivation in 53% and 30% respectively. Febrile neutropenia was seen in 20% and grade 4 thrombocytopenia in 12 % of cycles. Conclusions: Although it has significant infectious toxicity, ALZ 30mg and DA-EPOCHin untreated PTCL is feasible and associated with a long-term favorable outcome in nodal but not extranodal or leukemic PTCL. A phase III study of ALZ 30mg with anthracycline-based therapy is ongoing and we await the results with interest.

High-Dose Chemotherapy and Autologuos Stem Cell Transplantation in Previously Untreated Peripheral T-Cell Lymphoma - Final Analysis of a Large Prospective Multicenter Study (NLG-T-01)

Abstract 331 Background and aims:Systemic peripheral T-cell lymphomas (PTCL) are malignancies responding poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by upfront high-dose chemotherapy supported by autologous stem-cell transplantation (HDT/ASCT) in PTCL, the Nordic Lymphoma Group conducted the, so far, largest PTCL-restricted prospective phase II study in previously untreated systemic PTCL. This is the final report of the NLG-T-01 study with a 5-years median follow up. Methods:Patients with previously untreated systemic PTCL aged 18–67 years were included. ALK-positive anaplastic large cell lymphoma (ALCL) cases were excluded. An induction regimen of six cycles of bi-weekly cyclophosphamide, doxorubicin, etoposide, vincristin and prednisone (CHOEP) was given. Age-based (>60 yrs) omission of etoposide was recommended. If in complete or partial remission, patients received high-dose chemotherapy with carmustine, etoposide, cytarabine and melphalan/cyclophosphamide (BEAM/BEAC) followed by HDT/ASCT. Results:A total of 166 patients with previously untreated PTCL were enrolled. Of these, 160 were histopathologically confirmed and included the following subtypes: PTCL-not otherwise specified (PTCL-NOS) (n=62; 39%), ALK-negative ALCL (n=31; 19%), angioimmunoblastic lymphoma (AIL) (n=30; 19%), enteropathy-associated T-cell lymphoma (n=21; 13%), panniculitis-like (n=6; 4%), T/NK nasal-type (n=5; 3%), and hepatosplenic (n=5; 3%). The M/F ratio was 2.0 and the median age 57 yrs (range 22–67 yrs). The majority of the cases presented with advanced-stage disease (81%), B-symptoms (59%) and elevated s-LDH (62%). Nevertheless, 71% of all patients had a good performance score (PS) (WHO 0–1) at inclusion. With regard to the International Prognostic Index (IPI), risk factor distribution was as follows: 1 factor n=45 (28%), 2 factors n=52 (32%), 3 factors n=30 (19%), 4–5 factors n=33 (21%). Of the 160 patients, a total of 114 (71%) underwent HDT/ASCT with 90 in complete remission at 3 months post-transplant. Early failures occurred in 26% of the patients. The treatment related mortality was low (4%). At a median follow-up of 60 months, 83 patients were alive. The median follow-up for deceased patients (N=77) was 9 months. The consolidated 5-yr overall (OS) and progression-free survival (PFS) values for the entire cohort were 51% and 44%, respectively. Best results were obtained in ALK-negative ALCL with 5-yr OS and PFS of 70% and 61%, respectively. IPI was a useful overall prognostic discriminator for the low/low-intermediate vs. intermediate-high/high groups with regard to 5-yr OS (p=0,047) and 5-yr PFS (p=0,029). If applied separately to each of the four major subtypes, IPI had a predictive value for OS in AIL (p=0,02) and for PFS in both AIL (p=0,02) and PTCL-NOS (p=0,03). The clinicopathological parameters that showed a significant impact on OS and PFS were: female gender (correlated with a better outcome), age (analyzed as continuous variable), PS≥2 (correlated with adverse outcome), and cytotoxic phenotype (correlated with adverse outcome in AIL). All these parameters retained their prognostic value at multivariate level, except for cytotoxic phenotype, where multivariate analysis could not be performed because of too small numbers. Conclusions:Dose-dense induction followed by HDT/ASCT is well tolerated and leads to long-term PFS in 44% of patients with systemic PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the present study population. Therefore, based on these results, dose-dense induction and HDT/ASCT should be considered in transplant-eligible PTCL patients. Disclosures:Jantunen:Genzyme: Honoraria.

Early Results of a Phase Ib/II Dose-Escalation Trial of Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphomas (PTCL)

Abstract 2673 Background:Romidepsin is a potent histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior systemic therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 previous phase II studies with overall response rates of 30–38% (Piekarz et al., Blood 2011;117:5827; Coiffier et al., Blood 2010;116(21S):114). The observed toxicity was mainly hematological and digestive. Prolongation of the QT interval has been reported. The aim of the present study was to evaluate the safety, tolerability and efficacy of escalating doses of romidepsin in association with CHOP in patients with previously untreated PTCL. Methods:Patients with biopsy-proven PTCL are planned to receive 8 cycles of CHOP (cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1–5) in association with escalating doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 on days 1 & 8 has been chosen as the starting dose. At least 3 patients are to be treated at each dose level, and 3 more at the same dose level if 1 of the first three exhibited dose-limiting toxicity (DLT) during the first 2 cycles. Results:Six patients (3 male, 3 female, aged 47 to 67) have been included so far and are analyzable for toxicity on the first two cycles. Diagnoses were: PTCL, not otherwise specified (n=3), angioimmunoblastic TCL (n=1), primary cutaneous CD4+ small-medium TCL (n=1), enteropathy-associated TCL (n=1). ECOG performance status was good (0–1) in all patients; 5/6 had stage IV disease; IPI score was 1 (n=1), 2 (n=3), 3 (n=1), 4 (n=1). Among the first 3 patients treated at the starting dose of 10 mg/m2, one exhibited a DLT (grade 3 malaise after cycle 2), thus 3 more patients were treated at this dose level. Among those 3, we observed 2 other DLTs: one grade 3 general status deterioration and grade 3 haematological toxicity lasting more than 7 days in the same patient, and one grade 4 hematological toxicity lasting more than 3 days. A total of 269 adverse events (AEs) were observed during 34 analyzable cycles. The most frequent AEs were: neutropenia n=22 (grade 3–4 =12), thrombocytopenia n=28 (grade 3–4 n=5), digestive complaints n=18 (no grade >2), and asymptomatic increase of liver enzymes n=7 (1 grade 3). The mean increase in the corrected QT interval between pre- and post-romidepsin EKGs was 19 ms (range −43 to +79). No clinically relevant cardiac event was reported. One patient progressed after 5 cycles, 2 have finished the 8 planned cycles and are both in CR, and 3 are still under treatment without evidence of progression. Conclusion:Romidepsin can be combined with CHOP without unexpected toxicity. The dose of 10 mg/m2 on days 1& 8 is associated with excessive hematological toxicity. The study is ongoing with a lower dose of 8 mg/m2 on day 1 & 8 of each cycle. Updated results will be presented at the meeting. Disclosures:Coiffier:CELGENE: Consultancy, Research Funding, Speakers Bureau; ALLOS THERAPEUTICS: Consultancy, Research Funding, Speakers Bureau; ESAI: Consultancy, Research Funding, Speakers Bureau.

Hemopoietic stem cell transplantation in T-cell malignancies: Who, when, and how?

Only in recent years has there been a specific focus on the treatment of T-cell lymphomas in general and peripheral T-cell lymphomas (PTCLs) in particular. An increasing number of PTCL-specific retrospective analyses have been reported, and the first data from PTCL-restricted prospective clinical trials have appeared more recently. In this context, the role of hemopoietic stem cell transplantation-primarily autologous but also allogeneic-has been investigated. High-dose therapy with autologous stem cell transplantation (HDT/ASCT) proved feasible in both relapsed/refractory and previously untreated PTCL. Overall results show a more favorable impact when HDT/ASCT is part of first-line therapy rather than salvage treatment. Reported outcomes have varied, often depending on the number of anaplastic large-cell lymphomas in the cohort. In addition, retrospective results usually focus on patients undergoing transplantation, whereas the fraction of patients with primary refractory or early relapsing disease is best described in the intention-to-treat analysis of prospective trials. This article reviews the most recent results of upfront HDT/ASCT consolidation in different subtypes of systemic PTCL. The data on allogeneic stem cell transplantation are more limited, but promising results have recently been reported in the setting of relapsed or primary refractory disease.

Controversies in the treatment of lymphoma with autologous transplantation.

High-dose therapy and autologous stem cell transplant (HDT-ASCT) is the standard of care for relapsed and refractory diffuse large B cell lymphoma and Hodgkin's lymphoma; however, the role for HDT-ASCT in the treatment of follicular lymphoma (FL), mantle cell lymphoma (MCL), and peripheral T cell lymphoma (PTCL) is controversial. In FL, phase II and randomized data support the use of HDT-ASCT in the relapsed setting and incorporation of rituximab into mobilization regimens and post-transplant maintenance appears to prolong remission durations. Allogeneic stem cell transplant remains the only curative treatment option and is appropriate for patients with high bone marrow disease burdens and refractory disease. In MCL, HDT-ASCT is most often administered up front, and phase II studies using intense immunochemotherapy followed by HDT-ASCT in first complete response (CR) have shown the most impressive outcomes. Complicating the situation, however, are data supporting up-front intensive immunochemotherapy without HDT-ASCT consolidation as well as a "watch and wait" strategy for selected patients. Finally, in PTCL, phase II data support treatment with HDT-ASCT in first CR, and it is rarely appropriate in the relapsed setting. Furthermore, disease status at the time of transplant likely impacts outcome; however, this needs to be evaluated further. Overall, HDT-ASCT is an important element of the treatment of relapsed FL and untreated MCL and PTCL; however, large prospective studies are needed to confirm its role and identify the most optimal induction, mobilization, and maintenance regimens for each disease.

Response and Survival Rates in Patients with Peripheral T-Cell Lymphoma Treated with Anthracycline-Based Regimens: A Comprehensive Meta-Analysis.

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non-Hodgkin lymphomas (NHL) for which CHOP-type chemotherapy remains the standard despite its suboptimal results, especially when compared to its outcome in B-cell NHL. The International Peripheral T-Cell Lymphoma Clinical and Pathologic Review Project questioned the role of anthracyclines in the treatment of PTCL. To address this issue, we conducted a systematic literature review and meta-analysis of first-line therapy for untreated PTCL patients examining the complete remission (CR) and overall survival (OS) rates with anthracycline-based regimens. Given the established favorable treatment outcome of anaplastic large cell lymphomas (ALCL) along with the heterogeneity in response and survival rates across PTCL subgroups, we focused our analyses on non-ALCL PTCL and performed subgroup meta-analyses on the outcomes of anthracycline-based regimens for patients with PTCL- not-otherwise-specified (NOS), angio-immunoblastic T-cell lymphoma (AITL) and NK/T-cell NHL.Methods: We searched the ASH and ASCO Annual Meeting Abstracts (2003–2006), MEDLINE (1/1996–6/2007), and Google Scholar. Each search used combinations of the term 'Peripheral T-Cell Lymphoma', 'PTCL', 'T Cell Lymphoma', 'Non Hodgkin Lymphoma', 'NK/T-cell lymphoma', 'Angioimminoblastic lymphoma', 'Anaplastic large cell lymphoma', 'Enteropathy-type T-cell lymphoma', 'Alk-negative', 'Non-Alk positive', 'Anthracycline', 'Doxorubicin', 'Adriamycin', 'Intensive Chemo Therapy', and 'CHOP'. Criteria for including studies were:1.Intervention with chemotherapy with or without radiotherapy2.Reporting in English of treatment outcome measures for patients with non-ALCL PTCL including CR rate, overall response (OR) rate, and at least one form of survival data.Extracted data included pre-treatment disease status, treatment regimen, median follow up time, progression free survival, overall survival, CR, OR and early treatment-related death. Abstracts subsequently published as papers were excluded. In meta-analyses of selected studies, summary CR and 5-year OS estimates were calculated based on the assumption of fixed effects and using the Mantel-Haenszel method.Results: Thirty-one studies meeting the inclusion criteria for this analysis were initially identified. These studies included data from 2912 patients. Twenty-five studies (n=2011) were evaluable for CR. Eighteen studies (n=1812) provided 5-year OS data. The estimated CR rate for anthracycline-based regimens among non-ALCL PTCL patients was 54.5% (95%CI 52.3%–56.8%), with subgroup CR rates as follows: AITL 54.7% (95%CI 47.3%–61.8%), NK/T 57.0% (95%CI 52.5%–61.5%), PTCL-NOS 55.6% (95%CI 51.8%–59.2%). The estimated 5-year OS for non-ALCL PTCL was 37.3% (95%CI 35.1%–39.6%), and for each subgroup was: AITL 36.5% (95%CI 31.7%–41.7%), NK/T 47.9% (95%CI 42.5%–53.5%), PTCL-NOS 34.0% (95%CI 30.2%–38.1%; Figure).Conclusions: Despite the reasonable CR rates induced by anthracycline-based regimens in PTCL, OS remains poor. Future clinical trials need to focus on subtype-specific treatments for increasing CR and strategies such as stem cell transplantation or maintenance therapy, capable of sustaining CRs. [Display omitted]

Dose-Dense Induction Followed by Autologous Stem Cell Transplant (ASCT) as 1st Line Treatment in Peripheral T-Cell Lymphomas (PTCL) - A Phase II Study of the Nordic Lymphoma Group (NLG).

Systemic PTCL, with the exception of alk-positive anaplastic large cell lymphoma (ALCL), have a poor prognosis. ASCT has been shown to have a favourable impact on relapsed PTCL. Therefore, the NLG designed a prospective multicenter phase II study to evaluate the impact of a dose-intensified induction schedule (6 courses of two-weekly CHOEP) consolidated in 1st PR/CR with high-dose therapy (BEAM) followed by ASCT in previously untreated systemic PTCL. This is the largest prospective PTCL-specific trial published so far. Newly diagnosed non-primary cutaneous PTCL cases aged 18–67 yrs were eligible for enrollment. Cases of alk-positive ALCL were excluded. From Oct 2001 to Feb 2006, 99 histologically confirmed PTCL cases were included in the study: PTCL unspecified (n=41), alk-neg ALCL (n=24), AILT (n=15), enteropathy-type (n=12), panniculitis-like (n=3), T/NK nasal-type (n=2), hepatosplenic (n=2). The M/F ratio was 1.8 and the median age 55 yrs (range 20–67 yrs). Although almost 2/3 of the cases presented with advanced-stage disease (62%), B-symptoms (61%) and/or elevated s-LDH (63%), the majority of them (65%) had a good performance score (WHO 0–1) at diagnosis. Of the 77 patients, where information was available for all 6 induction courses, 68 (88%) were in CR (31) or PR (37) after the 3rd and 66 (86%) after the 6th course. A total of 58 patients (75%) went through ASCT indicating that at least a fourth of this younger patient cohort has a primary refractory disease and fails therapy before reaching the transplant. Treatment-related toxicity after both induction and high-dose treatment was manageable. Of the 58 transplanted patients, 50 (86%) were still in remission at re-evaluation short after transplant. In 39 patients follow-up data one year post-transplant were available: 30 are still in CR and 9 have relapsed, suggesting that post-transplant relapses probably account for another 25% of the original patient cohort. In conclusion, the present data indicate that a time- and dose-intensified schedule is feasible and effective in previously untreated systemic PTCL. Continuous remissions are not uncommon, but a longer follow-up is needed to further characterize long-term remission rates and evaluate their impact on time-to-treatment failure and overall survival.

CHOP/CHOEP-14 followed by consolidation with alemtuzumab in untreated aggressive T-cell lymphomas (DSHNHL 2003–1): Feasibility and toxicity of a phase II trial of the German High Grade Non-Hodgkin’s Lymphoma Group DSHNHL

7538 Background: The clinical course of peripheral T-cell lymphomas (PTCL) is unfavourable. Treatment protocols developed for aggressive B-NHL are employed, with significantly worse outcomes. The MoAb alemtuzumab (CAM) has shown promising activity in T-NHL, although its use may be complicated by severe infections. Methods: In 2003, the DSHNHL group initiated a prospective multicenter phase II trial for previously untreated PTCL. Six cycles of either CHOEP-14 (&lt; 60 y) or CHOP-14 (&gt; 60 y) with G-CSF support are followed by a short consolidation course with CAM, when either a CR or a good PR has been achieved. Inclusion criteria: PTCL-NOS, AILD, intestinal T-NHL, anaplastic large cell T-NHL (ALK negative); age 18–70 y; all IPIs; ECOG PS 0–3. The primary endpoint is feasibility, measured by occurrence SAE and protocol adherence. Secondary endpoints are remission rate, TTF, OS, DFS, tumor control and TRM. CAM is given at a total dose of 133 mg over 4 weeks. Prophylaxis against PCP and herpes infections is mandatory during CAM therapy and is continued until CD 4 cells are &gt; 200/μl. CMV-positive patients are monitored weekly. Results: 35 (of the planned 37) pts have been enrolled, 31 are evaluable. 5/31 pts are still undergoing chemotherapy. 7/31 pts had progressive disease or NC under/after chemotherapy and did not receive CAM. 18 of the 19 pts who achieved a CR/PR (15/4) received CAM. 12 of the CAM pts are in continuous CR, 7 had progressive disease or relapsed. There was no treatment-related death. Of 7 registered SAEs, 3 were related to chemotherapy, 4 to CAM (1 fungal pneumonia, 2 CMV pneumonias, 1 bacterial sepsis after dental procedure). Other CAM side effects were: Herpes Zoster (1), CMV-reactivation (1), grade III-IV neutropenias (2). All pts recovered with appropriate treatment. Conclusion: Preliminary analysis demonstrates that the combination of CHO/E/P-14 followed by a short course of CAM consolidation therapy is feasible without TRM. The adverse effects related to infections can be severe but manageable upon careful monitoring and close follow-up. The phase II trial will close in 4/2006, to be followed by a randomized phase III trial of A-CHOP-14 vs CHOP-14. No significant financial relationships to disclose.

Elevated Peripheral Blood (PB) Cytomegalovirus (CMV) Viral Loads and Reduced CD8+ T-Cell Counts Are Common Findings in T-Cell Lymphoma before Initiation of Therapy.

Background. T-cell lymphomas are often associated with abnormal T-cell responses. A viral etiology for certain subsets of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL) has been proposed, but viral isolates from fresh malignant T-cells are rare. Recently, a significant association between cytomegalovirus (CMV) seropositivity and CTCL was observed (Herne et.al. Blood 101(6):2132), suggesting a pathogenic role for CMV. However, no study to date has examined the incidence of CMV viremia in untreated CTCL and PTCL. Over the last 12 months we analyzed CMV viral loads in patients with CTCL or PTCL prior to initiation of systemic therapy to determine the frequency of CMV viremia and study the relationship between CMV viremia and cellular immune status, as defined by the absolute PB CD8+ T-cell count.Methods. A total of 56 patients with either CTCL (n=41) or PTCL (n=15) were assayed for whole blood quantitative CMV viral loads using a hybrid capture assay for CMV DNA (Digene). PB immunophenotyping by flow cytometry was used to determine absolute CD8+ T-cell counts. In-situ PCR was used to detect CMV DNA in tumor samples.Results. Only 2/56 patients had symptoms consistent with CMV reactivation at the time of the assay. Elevated CMV viral loads were seen in 15/56 (27%) of patients with a patient/cutoff ratio range of 1.0–107.6 and a median of 1.52 for CTCL and 2.14 for PTCL (>1.0 = positive). While all 15 patients with CMV viremia had positive serology for CMV, only 16/41 patients without elevated CMV viral loads were seropositive for CMV. Thus, although CMV viremia paralleled CMV seropositive status, the overall seroprevalence of CMV in this cohort 31/56 (55.3%) was not significantly different from that of the general population. The absolute CD8+ T-cell count was <200/mm3 in 8/15 (53.3%) patients and there was a significant relationship between lower CD8+ T-cell counts and higher CMV titers (p<.003). None of the 4 tumor samples tested from patients with elevated CMV viral loads (3 CTCL and 1 PTCL) was positive for CMV DNA.Conclusions. We found that CMV seroprevalence in this cohort of PTCL and CTCL was not greater than that reported in the general population (55.3%). However, we report a previously undescribed high frequency (27%) of CMV viremia, before systemic therapy, and a significant correlation between higher CMV viral loads and degree of CD8+ T-cell lymphopenia. Whether this association reflects a yet to be defined pathogenic role of CMV in T-cell lymphoma or is simply the result of decreased T-cell immunosurveillance remains to be established. The absence of CMV DNA in a limited number of tumor samples from patients with elevated viral load does not support a direct pathogenic role of CMV, although a larger study is needed to confirm this hypothesis. The correlation between lower CD8+ T-cells and CMV viral load suggests defective T-cell immunosurveillance against CMV. A prospective quantitative monitoring study of CMV-specific T-cell responses, CMV DNA viral loads and expression in tumor cells from patients with T-cell lymphoma and appropriate controls (normal volunteers and patients with other hematological malignancies) is in development.