Event free survival at 24 months is a strong surrogate prognostic endpoint of peripheral T cell lymphoma

Event free survival at 24 months (EFS24) has been described as a powerful predictor for outcome in several subtypes of B cell lymphoma. However, it was limitedly described in T cell lymphoma. We explored the implication of EFS24 as a predictor marker for peripheral T cell lymphoma (PTCL). We reviewed 293 systemic PTCL patients at 13 nationwide major university hospitals in Thailand from 2007 to 2014. The median event free survival (EFS) and overall survival (OS) of PTCL patients in our cohort was 16.3 and 27.7 months with corresponding 2‐year EFS and 2‐year OS of 45.8% and 51.9%, respectively. A total of 118 patients achieved EFS24 (no events during the first 24 mo). Patients who achieved EFS24 had better OS than patients who did not (2‐y OS 92% vs 18.8%; HR, 0.1; P < .001). The standardized mortality ratio of patients achieving EFS24 was 18.7 (95% CI, 14.6‐22.8). Multivariable analysis demonstrated performance status, histologic subtype, remission status, and EFS24 achievement as independent predictors for OS. Our study affirmed the value of EFS24 as a powerful prognostic factor for PTCL. Further validation in prospective study setting is warranted.     

Phase 2 trial of combined cisplatin,etoposide, gemcitabine,and methylprednisolone (PEGS) in peripheral T‐cell non‐Hodgkin lymphoma

BACKGROUND:

Patients with peripheral T‐cell lymphomas (PTCLs) have inferior progression‐free survival (PFS) and overall survival (OS) compared with patients who have aggressive B‐cell non‐Hodgkin lymphoma. Because PTCLs over express multidrug resistance gene 1/P‐glycoprotein (MDR‐1/P‐gp), we devised platinum, etoposide, gemcitabine, and methylprednisolone (PEGS) with agents that are not substrates of the efflux pump. Gemcitabine was included because of its excellent single‐agent activity in PTCL.

METHODS:

Patients who had PTCL with stage II bulky disease, stage III or IV disease with extra‐nodal, nodal, and transformed cutaneous presentations were eligible. Patients received intravenous cisplatin 25 mg/m² on days 1 through 4, etoposide 40 mg/m² on days 1 through 4, gemcitabine 1000 mg/m² on day 1, and methylprednisolone 250 mg on days 1 through 4 of a 21‐day cycle for 6 cycles.

RESULTS:

In total, 34 patients were enrolled, 33 were eligible, and 79% were newly diagnosed. Histologic types were PTCL not otherwise specified (n = 15), anaplastic lymphoma kinase (ALK)‐negative anaplastic large cell lymphoma (n = 4), angioimmunoblastic T‐cell lymphoma (n = 6), or other T‐cell non‐Hodgkin lymphomas (n = 8). Adverse events included 1 grade 5 infection with grade 3 or 4 neutropenia and 9 grade 4 hematologic toxicities. The overall response rate was 39% (47% in PTCL not otherwise specified, 33% in angioimmunoblastic T‐cell lymphoma, 25% in ALK‐negative and 38% in other T‐cell non‐Hodgkin lymphomas). The PFS rate at 2 years was 12% (95% confidence interval, 0.1%‐31%), and the median PFS was 7 months. The OS rate at 2 years was 30% (95% confidence interval, 8%‐54%), and the median OS was 17 months. Immunohistochemical analysis of P‐gp expression revealed strong positivity in a subset of lymphoma cells (n = 6) and tumor endothelium (n = 25).

CONCLUSIONS:

Overall, PEGS was well tolerated, but OS was not considered promising given the design‐specified targets. These results may serve as a benchmark for future comparisons for non‐CHOP regimens. Cancer 2013. © 2012 American Cancer Society.     

Correlation of pretransplant and early post‐transplant response assessment with outcomes after reduced‐intensity allogeneic hematopoietic stem cell transplantation for non‐Hodgkin's lymphoma

BACKGROUND:

Chemotherapy sensitivity, defined simply as at least a partial response to chemotherapy, is an important outcome predictor for non‐Hodgkin lymphoma (NHL) patients undergoing reduced‐intensity allogeneic hematopoietic stem cell transplantation (allo‐HCT). The authors hypothesized that further differentiation of chemotherapy sensitivity by specific response, complete remission (CR) versus partial remission (PR) versus stable disease (SD) versus progression of disease (PD), correlates with post‐transplant outcomes.

METHODS:

The impact of pretransplant and early (28 days) post‐transplant disease response on transplant outcomes was analyzed in 63 NHL patients treated with reduced‐intensity allo‐HCT.

RESULTS:

The 3‐year event‐free survival (EFS) and overall survival (OS) (median potential follow‐up after reduced‐intensity allo‐HCT = 58 months) for all patients was 37% and 47%, respectively. The 3‐year EFS based on pretransplant response was: CR = 50%; PR = 66%; SD = 18%; no patient with PD pretransplant reached 3‐year follow‐up. The 3‐year OS based on pretransplant response was: CR = 63%; PR = 69%; SD = 45%. The 3‐year EFS based on post‐transplant response was: CR = 57%; PR = 32%; SD = 33%; no patient with PD post‐transplant reached 3‐year follow‐up. The 3‐year OS based on post‐transplant response was: CR = 65%; PR = 43%; SD = 50%. In multivariate analyses, pretransplant response was the best predictor of EFS (P < .0001). Pretransplant response (P < .0001) and age (P = .0035) were jointly associated with OS.

CONCLUSIONS:

These data suggest that NHL patients with pretransplant SD, generally considered inappropriate candidates, may benefit from reduced‐intensity allo‐HCT, and patients with pretransplant PD should only receive this therapy in clinical trials. Cancer 2010. © 2010 American Cancer Society.     

Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation.

We report the results of two prospective phase II studies investigating the role of high-dose sequential chemotherapy, followed by autologous stem cell transplantation (ASCT) in 62 patients with advanced stage peripheral T-cell lymphomas (PTCLs) at diagnosis. Conditioning regimen consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) or carmustine, etoposide, Ara-C and melphalan followed by peripheral blood stem cell autografting. In an intent-to-treat analysis, 46 out of 62 patients (74%) completed the whole programme, whereas 16 patients did not undergo ASCT, mainly because of disease progression. At a median follow-up of 76 months, the estimated 12-year overall (OS), disease-free and event-free survival (EFS) were 34, 55 and 30%, respectively. OS and EFS were significantly better in patients with anaplastic lymphoma-kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL), as compared with the remaining PTCL. Multivariate analysis showed that patients attaining complete remission (CR) before ASCT had a statistically significant benefit in terms of OS and EFS (P<0.0001). Overall treatment-related mortality rate was 4.8%. In conclusion, our findings indicate (1) up-front high-dose therapy and ASCT are feasible, but could induce a high rate of long-term CR only in patients with ALK-positive ALCL and (2) the achievement of CR before autografting is a strong predictor of better survival.     

Romidepsin for the Treatment of Peripheral T‐Cell Lymphoma

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis in most subtypes. Diagnosis of this rare disease by expert hematopathologists improves accuracy of subtyping, and referral to academic or specialty centers is recommended. Many patients, however, will receive treatment in the community, and knowledge of approved agents is key to optimizing therapeutic approaches for all patients. There is no current standard of care for patients with PTCL and no approved therapies for first-line treatment. Although many patients initially respond to induction chemotherapy, responses are often brief, and many patients relapse or become treatment refractory. For patients with relapsed or refractory PTCL, achievement of durable responses is challenging, and there are few treatment options. Romidepsin is a histone deacetylase inhibitor approved by the U.S. Food and Drug Administration for the treatment of patients with cutaneous T-cell lymphoma who have received one prior systemic therapy or more and patients with PTCL who have received one prior therapy or more. Approval of romidepsin for PTCL was based on a pivotal phase II study of patients with relapsed or refractory PTCL (n = 131) that demonstrated an objective response rate of 25% including 15% with complete response; responses lasted a median of >2 years. Long-term responses to romidepsin were achieved in patients regardless of baseline characteristics, including subtype, heavy pretreatment, response to prior therapy, or advanced disease. Common adverse events included hematologic abnormalities, gastrointestinal or asthenic conditions, and infections; romidepsin was not correlated with clinically meaningful QT prolongation or electrocardiogram abnormalities.

Implications for Practice:

Due to the rarity, severity, and heterogeneous nature of peripheral T-cell lymphoma (PTCL), diagnosis by expert hematopathologists is preferred, and referral to specialty centers is recommended. Many patients, however, will receive treatment in the community, and community oncologists play a key role in the recognition and treatment of PTCL. Knowledge of approved agents is key for optimizing therapeutic approaches. This review provides an overview of PTCL and an in-depth examination of romidepsin, a histone deacetylase inhibitor approved for the treatment of relapsed or refractory PTCL, and highlights difficulties of diagnosis and optimization of treatment modalities for patients with PTCL.     

Complete remission with romidepsin in a patient with T‐cell acute lymphoblastic leukemia refractory to induction hyper‐CVAD

T‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL) are neoplasms that originate from T‐cell precursors. Outcomes in adult patients with T‐ALL/LBL remain unsatisfactory; early relapse following intensive induction chemotherapy is a concern, and patients with relapsed or refractory disease have a poor prognosis. Romidepsin is a potent, class 1 selective histone deacetylase inhibitor approved for the treatment of patients with peripheral T‐cell lymphoma who have had ≥1 prior therapy and patients with cutaneous T‐cell lymphoma who have had ≥1 prior systemic therapy. Here, we report the case of an adult patient with T‐ALL refractory to induction hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD). Treatment with romidepsin was initiated, and romidepsin in combination with hyper‐CVAD resulted in complete remission, with mild tumor lysis syndrome as the only detectable additional toxicity. The patient eventually underwent allogeneic stem cell transplant while in first complete remission. Prior studies have shown that romidepsin is capable of inducing durable responses with manageable toxicities in patients with mature T‐cell lymphomas. This case study describes the successful use of romidepsin in combination with hyper‐CVAD in an adult patient with refractory T‐ALL and highlights the activity of romidepsin in the T‐cell lineage. The potential of romidepsin‐containing regimens in patients with T‐ALL/LBL deserves further study.     

Clinicopathological analysis of 17 primary cutaneous T‐cell lymphoma of the γδ phenotype from Japan

Primary cutaneous γδ T‐cell lymphoma (PCGD‐TCL) is an aggressive lymphoma consisting of clonal proliferation of mature activated γδ T‐cells of a cytotoxic phenotype. Because primary cutaneous γδ T‐cell lymphoma is a rare disease, there are few clinicopathological studies. In addition, T‐cell receptor (TCR) γδ cells are typically immunostained in frozen sections or determined by TCRβ negativity. We retrospectively analyzed 17 primary cutaneous T‐cell lymphomas of the γδ phenotype (CTCL‐γδ) in a clinicopathological and molecular study using paraffin‐embedded sections. Among 17 patients, 11 had CTCL‐γδ without subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) features and six had CTCL‐γδ with SPTCL features. Immunophenotypically, some significant differences were found in CD8 and CD56 positivity between our patient series of CTCL‐γδ patients with SPTCL features and SPTCL‐γδ patients described in the previous literature. A univariate analysis of 17 CTCL‐γδ patients showed that being more than 60 years old, presence of visceral organ involvement, and small‐to‐medium cell size were poor prognostic factors. In addition, the 5‐year overall survival rate was 42.4% for the CTCL‐γδ patients without SPTCL features and 80.0% for those with SPTCL features. Consequently, there was a strikingly significant difference in overall survival among SPTCL, CTCL‐γδ with SPTCL features and CTCL‐γδ without SPTCL features (P = 0.0005). Our data suggests that an indolent subgroup may exist in CTCL‐γδ. Studies on more cases, including those from other countries, are warranted to delineate the clinicopathological features and the significance in these rare lymphomas.     

Biweekly THP‐COP therapy for newly diagnosed peripheral T‐cell lymphoma patients

Pirarubicin tetrahydropyranyl adriamycin (THP‐ADR) is an analogue of doxorubicin. This agent exhibits activity against some doxorubicin‐resistant cell lines. We performed a phase II study of biweekly THP‐COP [50 mg/m² pirarubicin, 750 mg/m² cyclophosphamide, 1.4 mg/m² vincristine (2.0 mg maximum) on day 1, and 100 mg/body predonisolone on days 1–5] in patients with peripheral T‐cell lymphoma (PTCL). Seventeen patients with newly diagnosed PTCL were enrolled. Histological diagnoses were of PTCL, not otherwise specified (n = 5), or angioimmunoblastic T‐cell lymphoma (n = 12). All diagnostic specimens including those of the historical control group were centrally reviewed by hematological pathologists. All patients received six cycles of biweekly THP‐COP. The patient group included 13 male and 4 female patients, with a median age of 62 years. The median follow‐up time in surviving patients was 30 months. Overall response rate was 94% with 15 cases of complete remission (88%). The 3‐year progression‐free survival and overall survival rates were 57% and 75%, respectively. The most frequent adverse events associated with biweekly THP‐COP were leukocytopenia (100%), neutropenia (100%), and lymphopenia (100%), followed by alopecia (92%) and anaemia (88%). All of these occurred only transiently, and the patients subsequently recovered. Biweekly THP‐COP is a safe and promising therapy for patients with newly diagnosed PTCL. This study is registered in a public database (UMIN000010485). Copyright © 2014 John Wiley & Sons, Ltd.     

Plasma soluble programmed death ligand 1 levels predict clinical response in peripheral T‐cell lymphomas

Immune checkpoints, including PD‐1/PD‐L1, play an important role in immunosuppression in various malignancies. Elevated levels of soluble programmed death ligand 1 (sPD‐L1) are associated with worse prognosis in multiple myeloma and diffuse large B cell lymphoma. Herein, the purpose of this study is to investigate the relationships between plasma sPD‐L1 levels and clinical response in peripheral T‐cell lymphoma (PTCL) patients. A total of 37 PTCL patients and 20 healthy volunteers were enrolled. Peripheral blood from patients was collected prior to systemic therapy. Plasma levels of sPD‐L1 and IFN‐γ were measured by enzyme‐linked immunosorbent assay (ELISA). PD‐L1 expression in tissues was detected by immunohistochemistry (IHC). Clinical response for patients was evaluated. ONCOMINE database analyses showed that PD‐L1 mRNA expression was significantly upregulated in PTCLs. The median sPD‐L1 level was 0.729 ng/mL for 20 healthy volunteers and 1.696 ng/mL for 37 PTCL patients which was significantly higher than that in healthy volunteers (0.000). The sPD‐L1 level was positively correlated with IFN‐γ level (0.000, r = 0.849) and was also positively associated with clinical staging (0.045), LDH level (0.003), and β2‐MG level (0.045). Patients with high sPD‐L1 level had lower overall response rate than those with low sPD‐L1 level (88.9% vs 50.0%, 0.022) and tended to have poorer PFS and OS. PD‐L1 expression in tissues matched very well with the sPD‐L1 level in PTCL patients. In conclusion, PTCL patients had higher sPD‐L1 level compared with healthy volunteers. High sPD‐L1 level was correlated with worse clinical response, suggesting that sPD‐L1 level was an underlying plasma biomarker to predict the prognosis for PTCL patients.     

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma

BACKGROUND:

Improved outcomes have recently been reported for rituximab (R) plus rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R‐EPOCH) chemotherapy in patients with human immunodeficiency virus (HIV)‐associated, aggressive B‐cell, non‐Hodgkin lymphoma (NHL). The objective of the current analysis was to assess whether patient selection or other factors contributed to this improvement and to identify patients who are at the greatest risk for lethal toxicity.

METHODS:

The authors performed a pooled analysis of 2 consecutive trials that included 150 patients with HIV‐associated NHL who received either R‐CHOP (n = 99; Acquired Immunodeficiency Syndrome [AIDS] Malignancy Consortium Trial 010 [AMC010]) or R‐EPOCH (n = 51; AMC034). Age‐adjusted International Prognostic Index (aaIPI), CD4 count at lymphoma diagnosis (<100/μL vs ≥100/μL), and treatment (R‐CHOP vs R‐EPOCH) were included as variables in a multivariate logistic regression model for complete response (CR) and in a Cox proportional hazards regression models for event‐free survival (EFS) and overall survival (OS).

RESULTS:

Features that were associated significantly with an improved CR rate and improved EFS and OS included a low aaIPI score and a baseline CD4 count ≥100/μL. When the analysis was adjusted for aaIPI and CD4 count, patients who received concurrent R‐EPOCH had improved EFS (hazard ratio [HR] 0.40; 95% confidence intervals [CI], 0.23, 0.69; P < .001) and OS (HR, 0.38; 95% CI, 0.21, 0.69; P < .01). Treatment‐associated death occurred significantly more often in patients with CD4 counts <50/μL (37% vs 6%; P < .01).

CONCLUSIONS:

The current analysis provided additional level 2 evidence supporting the use of concurrent R‐EPOCH in patients with HIV‐associated lymphoma and a CD4 count >50/μL, and the results support the design of an ongoing phase 3 trial comparing concurrent R‐EPOCH with R‐CHOP in immunocompetent patients with diffuse large B‐cell lymphoma (National Clinical Trial no. NCT00118209). Cancer 2012. © 2011 American Cancer Society.     

Response and survival benefit with chemoimmunotherapy in Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma

Epstein‐Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) is a haematologic malignancy with poor prognosis when treated with chemotherapy. We evaluated response and survival benefits of chemoimmunotherapy in EBV‐positive DLBCL patients. A total of 117 DLBCL patients were included in our retrospective analysis; 33 were EBV‐positive (17 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R‐CHOP] and 16 with CHOP), and 84 were EBV‐negative (all treated with R‐CHOP). The outcomes of interest were complete response (CR) and overall survival (OS) in EBV‐positive DLBCL patients (R‐CHOP versus CHOP) and in DLBCL patients treated with R‐CHOP (EBV‐positive vs EBV‐negative). There were no differences in the clinical characteristics between EBV‐positive and EBV‐negative DLBCL patients. Among EBV‐positive DLBCL patients, R‐CHOP was associated with higher odds of CR (OR 3.14, 95% CI 0.75‐13.2; P = .10) and better OS (hazard ratio 0.30, 95% confidence interval [CI] 0.09‐0.94; P = .04). There were no differences in CR rate (OR 0.52, 95% CI 0.18‐1.56; P = .25) or OS (hazard ratio 0.93, 95% CI 0.32‐2.67; P = .89) between EBV‐positive and EBV‐negative DLBCL patients treated with R‐CHOP. Based on our study, the addition of rituximab to CHOP is associated with improved response and survival in EBV‐positive DLBCL patients. Epstein‐Barr virus status does not seem to affect response or survival in DLBCL patients treated with R‐CHOP.     

CHOP or THP‐COP regimens in the treatment of newly diagnosed peripheral T‐cell lymphoma,not otherwise specified: a comparison of doxorubicin and pirarubicin

The CHOP regimen consisting of cyclophosphamide, doxorubicin (DOX), vincristine and prednisolone has been the most used regimen for peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS). Pirarubicin [tetrahydropyranyladriamycin (THP)], a derivative of DOX, is an anthracycline with reportedly less cardiotoxicity than DOX. Here, we confirmed the efficacy of THP‐COP using THP instead of DOX in the treatment of PTCL‐NOS. The study protocol employed a retrospective, consecutive entry design. We retrospectively analysed 56 patients with PTCL‐NOS who had received THP‐COP or CHOP. These regimens were performed every 21 days. Twenty‐nine patients received THP‐COP, and 27 received CHOP. There were no significant differences in known prognostic factors, including in the International Prognostic Index (IPI) and the prognostic index for T‐cell lymphoma (PIT), between the two groups. Complete remission rates in patients with THP‐COP and CHOP were 52% in both groups; the 3‐year overall survival (OS) rates were 67% and 52% (p = 0.074), and the 3‐year progression‐free survival (PFS) rates were 51% and 29% (p = 0.070), respectively. In patients with low IPI (low or low‐intermediate), THP‐COP had significantly better 3‐year OS (100% vs. 64%; p < 0.001) and 3‐year PFS (75% vs. 33%; p < 0.05) than CHOP. Similar differences between THP‐COP and CHOP were observed in patients with a low PIT (groups 1 or 2). Our study showed that THP‐COP produced results equivalent to CHOP regarding efficacy and safety in patients with PTCL‐NOS. In patients with low IPI or PIT, THP‐COP resulted in significantly better prognosis. Copyright © 2015 John Wiley & Sons, Ltd.     

Results from a multicenter,open-label,pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma

BackgroundChidamide is a novel benzamide type of subtype-selective histone deacetylase (HDAC) inhibitor with unique mechanisms of action compared with marketed HDAC inhibitors. This phase II study was to evaluate the efficacy and safety of chidamide in relapsed or refractory peripheral T-cell lymphoma (PTCL) in Chinese population.Patients and methodsPatients with relapsed or refractory PTCL of different subtypes received chidamide of 30 mg orally twice per week. The primary end point was overall response rate (ORR). Responding patients should be confirmed at least 4 weeks after the criteria of the response were first met, and were reviewed by an independent review committee.ResultsEighty-three patients were enrolled and 79 patients with eligible PTCL histology were for efficacy assessments. Patients enrolled over 10% were with subtypes of PTCL not otherwise specified (34%), anaplastic large-cell lymphoma (22%), extranodal natural killer (NK)/T-cell lymphoma, nasal type (20%), or angioimmunoblastic T-cell lymphoma (AITL, 13%). The ORR was 28% (22 of 79) including 14% (11 of 79) with complete response/unconfirmed complete response (CR/CRu). Median progression-free survival and overall survival were 2.1 and 21.4 months, respectively. AITL patients tended to have higher ORR (50%) and CR/CRu rate (40%), as well as more durable responses, to chidamide treatment. Most adverse events (AEs) were grade 1 or 2, and AEs ≥grade 3 that occurred in ≥10% patients were thrombocytopenia (22%), leucopenia (13%) and neutropenia (11%), respectively.ConclusionChidamide represents a novel oral benzamide class of HDAC inhibitor with significant single-agent activity and manageable toxicity in relapsed or refractory PTCL, and provides a much needed treatment option in this indication in China. Results led to China Food and Drug Administration approval of chidamide in this indication.     

Refractory diffuse large B‐cell lymphoma after first‐line immuno‐CT: Treatment options and outcomes

In the rituximab era, one‐third of diffuse large B‐cell lymphoma patients experience relapse/refractory disease after first‐line anthracycline‐based immunochemotherapy. Optimal management remains an unmet medical need. The aim of this study was to report the outcomes of a cohort of refractory patients according to their patterns of refractoriness and the type of salvage option. We performed a retrospective analysis, which included 104 diffuse large B‐cell lymphoma patients treated at Lyon Sud University Hospital (2002‐2017) who presented with refractory disease. Refractoriness was defined as progressive/stable disease during first‐line treatment (primary refractory, N = 47), a partial response after the end of first‐line treatment that required subsequent treatment (residual disease, N = 19), or relapse within 1 year of diagnosis after an initial complete response (CR) (early relapse, N = 38). The 2‐year overall survival (OS) rates for primary refractory, early relapse, and residual disease patients were 27%, 25%, and 52%, respectively, while the event‐free survival rates for those groups were 13%, 13%, and 42%, respectively. In a univariate analysis, lactate dehydrogenase level, Ann Arbor stage, poor performance status, high age‐adjusted International Prognostic Index score, and age > 65 years were associated with shorter OS. The use of rituximab and platinum‐based chemo during the first salvage treatment was associated with prolonged OS. In a multivariate analysis, age (HR:2.06) and rituximab use (HR:0.54) were associated with OS. Among patients <65 years who achieved a CR, autologous stem‐cell transplant was associated with higher 2‐year OS (90% vs 74%, P = 0.10). Patients who were treated with a targeted therapy in the context of a clinical trial after second‐line treatment had a higher 2‐year OS (34% vs 19%, P = 0.06). In conclusion, patients with primary refractory disease or early relapse have very poor outcomes but may benefit from rituximab retreatment during the first salvage treatment.     

How to predict the outcome in mature T and NK cell lymphoma by currently used prognostic models?

To select an appropriate prognostic model in the treatment of mature T- and natural killer (NK) -cell lymphoma (peripheral T-cell lymphoma (PTCL) and NK-/T-cell lymphoma (NKTCL)) is crucial. This study investigated the usefulness of Ann Arbor staging classification International prognostic index (IPI), prognostic index for T-cell lymphoma (PIT) and International peripheral T-cell lymphoma Project score (IPTCLP). Between 2000 and 2009, 176 patients (122 males) with PTCL and NKTCL were diagnosed and treated from a single institute in Taiwan. The correlation between complete response (CR) rate, 3-year overall survival (OS), early mortality rate and four prognostic models was analyzed. Thirty-one patients received hematopoietic stem cell transplantation (HSCT) and were analyzed separately. Three-year OS rate was 34.7%, and anaplastic large-cell lymphoma harbored better outcome than others. IPI score had the lowest Akaike information criterion value (1081.197) and was the best score in predicting OS and early mortality (P=0.009). Ann Arbor stage classification can predict CR rate more precisely (P=0.006). OS was significantly better in patients who received HSCT, even in patients with unfavorable features compared with chemotherapy alone. All prognostic models were useful to evaluate the outcome of patients with PTCL and NKTCL but IPI score did best in predicting OS in PTCL and PIT score in NKTCL. This study also supported the role of HSCT in patients with high-risk or refractory PTCL or NKTCL.     

Comparison of four prognostic scores in peripheral T-cell lymphoma

BackgroundTo compare the usefulness of four prognostic scores in patients with peripheral T-cell lymphoma (PTCL) from a single institution.Patients and methodsOne hundred twenty-one patients (77 male/36 female, median age 53 years) with PTCL [anaplastic large-cell lymphoma (ALCL) 21, PTCL not otherwise specified 56 and other 44)]. Complete response (CR) rate and 5-year overall survival (OS) were 41% and 31%, respectively. International Prognostic Index (IPI), Prognostic Index for T-cell lymphoma (PIT), International peripheral T-cell lymphoma Project score (IPTCLP) and modified Prognostic Index for T-cell lymphoma (mPIT) were calculated as in the original references. mPIT was only assembled to 41 patients in whom Ki-67 immunostaining was available. ALCL patients were analyzed separately.ResultsConcordance among IPI, PIT and IPTCLP was 52% for low-risk group, 27% for low/intermediate-risk group, 20% for high/intermediate-risk group and 14% for high-risk group. IPI, PIT and IPTCLP predicted CR, with IPI being the best score in logistic regression. Neither Ki-67 immunostaining nor mPIT predicted CR. Five-year OS (low-risk versus intermediate- or high-risk categories) according to IPI, PIT, IPTCLP and mPIT were 52% versus 45%, 75% versus 49%, 58% versus 20% and 39% versus 0%, respectively. IPTCLP was the best score for OS in multivariate analysis.ConclusionAll the scores demonstrated their usefulness to assess the outcome of patients with PTCL, with IPTCLP being the most significant to predict OS.     

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy

BackgroundOptimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear.Patients and methodsWe examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses.ResultsPTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I–II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34–0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22–0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14–0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17–0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission.ConclusionsThis analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.     

Real‐world experience with decitabine as a first‐line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy

Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real‐world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient‐level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first‐line decitabine therapy at the registered schedule of 20 mg/m²/iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all‐cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy‐one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable‐intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse‐free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7‐16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13‐2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06‐1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first‐line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.     

Multicenter phase II study of bendamustine for relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Bendamustine is a unique cytotoxic agent that has demonstrated efficacy in the treatment of indolent B‐cell non‐Hodgkin lymphomas (B‐NHLs). In this multicenter phase II trial, the efficacy and safety of bendamustine were evaluated in Japanese patients with relapsed or refractory indolent B‐NHL or mantle‐cell lymphoma (MCL). Patients received bendamustine (120 mg/m²) on days 1–2 of a 21‐day cycle, for up to six cycles. The primary endpoint was the overall response rate (ORR) as assessed by an extramural committee according to International Workshop Response Criteria (IWRC). Secondary endpoints included complete response (CR) rate, ORR according to Revised Response Criteria (revised RC), progression‐free survival (PFS), and safety. Fifty‐eight patients with indolent B‐NHL and 11 with MCL were enrolled. By IWRC, bendamustine produced an ORR of 91% (95% confidence interval [CI], 82–97%; 90% and 100% in patients with indolent B‐NHL and MCL, respectively), with a CR rate of 67% (95% CI, 54–78%). ORR and CR rates according to revised RC were 93% (95% CI, 84–98%) and 57% (95% CI, 44–68%), respectively. After a median follow‐up of 12.6 months, median PFS had not been reached. Estimated PFS rates at 1 year were 70% and 90% among indolent B‐NHL and MCL patients, respectively. Bendamustine was generally well tolerated. Reversible myelosuppression, including grade 3/4 leukopenia (65%) and neutropenia (72%), was the most clinically significant toxicity observed. Common non‐hematologic toxicities included mild gastrointestinal events and fatigue. These results demonstrate the high efficacy and tolerability of single‐agent bendamustine in relapsed patients with indolent B‐NHL or MCL histologies. (ClinicalTrials.gov ID: NCT00612183). (Cancer Sci 2010;)     

Utility of18fluoro-deoxyglucose positron emission tomography for prognosis and response assessments in a phase 2 study of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma

This study examined the utility of PET scans for assessing prognosis and response to treatment in patients with relapsed/refractory PTCL receiving romidepsin. For patients with stable disease or partial response by conventional criteria, PET status better differentiated durability of response than conventional response category. Routine PET use may aid in treatment planning in patients with PTCL.BackgroundFor patients with peripheral T-cell lymphoma (PTCL), the value of¹⁸fluoro-deoxyglucose positron emission tomography (FDG-PET) scans for assessing prognosis and response to treatment remains unclear. The utility of FDG-PET, in addition to conventional radiology, was examined as a planned exploratory end point in the pivotal phase 2 trial of romidepsin for the treatment of relapsed/refractory PTCL.Patients and methodsPatients received romidepsin at a dose of 14 mg/m² on days 1, 8, and 15 of 28-day cycles. The primary end point was the rate of confirmed/unconfirmed complete response (CR/CRu) as assessed by International Workshop Criteria (IWC) using conventional radiology. For the exploratory PET end point, patients with at least baseline FDG-PET scans were assessed by IWC + PET criteria.ResultsOf 130 patients, 110 had baseline FDG-PET scans, and 105 were PET positive at baseline. The use of IWC + PET criteria increased the objective response rate to 30% compared with 26% by conventional radiology. Durations of response were well differentiated by both conventional radiology response criteria [CR/CRu versus partial response (PR),P = 0.0001] and PET status (negative versus positive,P < 0.0001). Patients who achieved CR/CRu had prolonged progression-free survival (PFS, median 25.9 months) compared with other response groups (P = 0.0007). Patients who achieved PR or stable disease (SD) had similar PFS (median 7.2 and 6.3 months, respectively,P = 0.6427). When grouping PR and SD patients by PET status, patients with PET-negative versus PET-positive disease had a median PFS of 18.2 versus 7.1 months (P = 0.0923).Conclusion(s)Routine use of FDG-PET does not obviate conventional staging, but may aid in determining prognosis and refine response assessments for patients with PTCL, particularly for those who do not achieve CR/CRu by conventional staging. The optimal way to incorporate FDG-PET scans for patients with PTCL remains to be determined.Trial registrationNCT00426764.