Treatment Of Aggressive non-Hodgkin Lymphoma Research Articles

Ultra-Hypofractionated Involved Site Radiation Therapy (ISRT) As Salvage or Bridging Therapy in Aggressive Non-Hodgkin Lymphomas

Introduction: Conventional fractionated radiation treatment (RT) to a total dose of 40-50 Gy in 20-25 fractions is typically recommended in the ‘definitive’ intent treatment of aggressive chemorefractory non-Hodgkin lymphoma. However, during the time of COVID-19, recommendations for hypofractionated courses (5-13 fractions) arose (Yahalom et al Blood 2020) as modern radiation techniques should allow similar total doses to be delivered safely in far fewer fractions. Our aim is to evaluate the outcomes and toxicities of ultra-hypofractionated (</=5 fractions) ‘definitive’ ISRT in aggressive non-Hodgkin lymphomas to see if this may be an acceptable alternate recommendation beyond COVID-19. Methods: We conducted an IRB-approved, retrospective review of all aggressive non-Hodgkin lymphoma patients treated at our institution with ‘definitive’ intent (40-50 Gy EQD2 with an α/β of 10) ultra-hypofractionated ISRT between April 2020 and July 2023. Demographic, disease-specific, and treatment-related variables were collected. Primary outcomes include objective response rate (ORR), defined as complete (CR) or partial response (PR) on post-RT positron emission tomography (PET) scans using the Lugano classification, local failure (LF), and radiation-related toxicity per CTCAE v5. Secondary outcomes include overall disease control and survival. Results: 26 ultra-hypofractionated radiation treatments were identified from 23 unique patients who were treated with ‘definitive’ intent ISRT (39.1% salvage, 30.4% early-salvage post CAR-T, and 30.4% bridging to SCT or CAR-T). The most common dose was 30 Gy in 5 fractions (96%); all patients were treated with IMRT with SBRT-type immobilization and image guidance as clinically indicated. The most common diagnosis was DLBCL (91%). 10/23 (43%) patients were female, the majority (82%) were ECOG 0-1 performance status, and the average age at time of RT was 68.9 years. 39% had all FDG-avid sites at the time of radiation treated. The median follow-up was 8.3 months (range 0.3-27.9 months). 26% of patients had acute radiation related toxicities, which were all grade 1-2 with the most common being fatigue (30%). There were no grade 3-4 toxicities, and no subacute or long-term toxicities. Initial local ORR was 20/21, or 95% (86% CR and 10% PR), while initial overall ORR was 12/21, or 57% (52% CR and 5% PR). At time of last follow up, only 1/24 (4%) of irradiated sites had local failure (2 data points N/A), with a TTLF of 1.5 months. 62% of patients had disease progression, with median time to disease progression of 1.5 months. At time of last follow up, 48% were dead, with a median time to death of 6.6 months. Conclusions: Ultra-hypofractionated ISRT in the ‘definitive’ intent treatment of aggressive non-Hodgkin lymphomas has excellent local tumor control and appears to be safe with minimal acute and subacute toxicities. In addition to patient convenience and cost effectiveness, short-course ISRT allows patients to quickly move on to next-line therapy when indicated. Prospective studies and long-term follow up are needed to further validate this as an alternative radiation treatment option.

Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients

AbstractThe survival of patients with aggressive non-Hodgkin lymphoma (NHL) is increasing, but the incidence of secondary cancer and late toxicity is poorly defined for those treated with cyclophosphamide-hydroxydaunomycin/doxorubicin-Oncovin-prednisone (CHOP)–like chemotherapy. From February 1984 to January 1998, 2837 patients with aggressive NHL received the control-arm chemotherapy adriamycin-cyclophosphamide-vindesine-bleomycin-prednisone (ACVBP) in 3 consecutive Groupe d’Etude des Lymphomes de l’Adulte (GELA) studies. With a median follow-up time of 74 months, the 5-year overall and event-free survival rates were 60% and 52%. Two hundred two occurrences of nonneoplastic late toxicity were reported, resulting in a 5.35% cumulative probability of incidence at 7 years. Eighty-one second tumors developed, for which the 7-year cumulative incidence rate was 2.75%; 64 were solid tumors, and 17 were hematologic malignancies. In multivariate analysis, age was the only risk factor for the second development of cancer. Epidemiologic analysis allowed a comparison of this NHL group with the general population. Considering all tumors, no excess of second cancer was observed. In the male population, however, there was an excess of lung cancer (standardized incidence ratio [SIR], 2.45; P < .001) and myelodysplastic syndrome/acute myelocytic leukemia (MDS/AML) (SIR, 5.65; P = .006), and in the female population there was an excess of MDS/AML (SIR, 19.9; P < .001). With a long follow-up, the ACVBP regimen was highly effective for the treatment of aggressive NHL. Increases occurred in secondary MDS/AML and in lung cancer among men.

Cardiovascular adverse events in patients with non-Hodgkin lymphoma treated with first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP with rituximab (R-CHOP): a systematic review and meta-analysis

Patients treated for non-Hodgkin lymphoma are at risk of cardiovascular adverse events, with the risk of heart failure being particularly high. A regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, with (R-CHOP) or without (CHOP) rituximab is the standard first-line treatment for aggressive non-Hodgkin lymphoma, and doxorubicin and cyclophosphamide are both associated with left ventricular dysfunction. The aim of this systematic review and meta-analysis was to evaluate the cardiovascular toxicity of this regimen. We systematically searched PubMed, EMBASE, and the Cochrane Library from database inception to June 3, 2019, for clinical trials and observational studies in adult patients with non-Hodgkin lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, and non-Hodgkin lymphoma not otherwise specified) that received first-line treatment with R-CHOP or CHOP. Studies reporting on cardiovascular adverse events and treatment-related cardiovascular mortality were included. Abstracts and articles not written in English were excluded. The main outcomes were the proportion of patients with grade 3-4 cardiovascular adverse events and heart failure. Meta-analyses of one-sample proportions were done in all patients receiving CHOP or R-CHOP. Subgroup analyses on summary estimates were done to determine the effect of number of CHOP or R-CHOP cycles, cycle interval, age, and sex. Of 2314 identified entries, 137 studies (21 211 patients) published between April, 1984, and June, 2019 were eligible (9541 patients treated with CHOP, 11 293 patients treated with R-CHOP, 377 both regimens used in the study; median follow-up 39·0 months [IQR 25·5-52·8]). From the included studies, 85 subgroups were treated with CHOP, 76 with R-CHOP, and in four studies both CHOP and R-CHOP were used without a subdivision in separate groups. The pooled proportion for grade 3-4 cardiovascular adverse events, based on 77 studies (n=14 351 patients), was 2·35% (95% CI 1·81-2·93; heterogeneity test Q=326·21; τ2=0·0042; I2=71·40%; p<0·0001). For heart failure, the pooled proportion, based on 38 studies (n=5936 patients), was 4·62% (2·25-7·65; heterogeneity test Q=527·33; τ2=0·0384; I2=95·05%; p<0·0001), with a significant increase in reported heart failure from 1·64% (95% CI 0·82-2·65) to 11·72% (3·00-24·53) when cardiac function was evaluated post-chemotherapy (p=0·017). 53 (39%) of 137 studies were rated as having high risk of bias for incomplete outcome data and 54 (39%) for selective reporting. The considerable increase of reported heart failures with cardiac monitoring, indicates that this complication often remains undiagnosed in patients with non-Hodgkin lymphoma who received first-line R-CHOP or CHOP. Our findings are of importance to raise awareness of this complication among clinicians treating patients with non-Hodgkin lymphoma and stresses the need for cardiac monitoring during and after chemotherapy. Prompt initiation of treatment for heart failure in the presymptomatic phase can mitigate the progression to more advanced heart failure stages. None.

Analysis of clinical efficacy and prognostic factors of double autologous hematopoietic stem cell transplantation in treatment of aggressive non-Hodgkin lymphoma

Objective To investigate the clinical efficacy and prognostic factors of double autologous hematopoietic stem cell transplantation (DAHSCT) in treatment of aggressive non-Hodgkin lymphoma (NHL). Methods From March 2001 to December 2014, a total of 48 patients with aggressive NHL who underwent scheduled DAHSCT in Tangdu Hospital, the Fourth Military Medical University were selected as the study subjects. Among them, 29 patients were male and 19 cases were female; and 22 patients were with B-cell non-Hodgkin lymphoma (B-NHL), 26 cases were with T-cell non-Hodgkin lymphoma (T-NHL). All 48 patients underwent the second autologous hematopoietic stem cell transplantation (auto-HSCT) within 2 to 6 months after receiving the first auto-HSCT. Retrospective analysis was used to collect clinical data from all patients, including age, occurrence of B symptoms, clinical staging of Ann Arbor/Cotswolds staging system, level of serum lactate dehydrogenase (LDH), international prognostic index (IPI) score, occurrence of extra-nodal lesions, and remission status of disease before the first and second auto-HSCT, etc.. Kaplan-Meier method was used to analyze the survival of 48 NHL patients. Univariate Cox regression analysis was used to analyze the factors that may influence the overall survival (OS) period of NHL patients after DAHSCT. According to the available research results and clinical experience, the further multivariate Cox regression analysis was carried out for the factors that were statistically significant in the univariate analysis, as well as some factors that were not statistically significant in the univariate analysis, but with clinical significance. Results ① All 48 aggressive NHL patients were collected enough peripheral blood stem cells, and got hematopoietic reconstitution after receiving auto-HSCT. In this study, the median number of CD34+ cells transfused was 3.40×106/kg [(2.70-8.70)×106/kg] in the first auto-HSCT and 3.68×106/kg [(2.95-8.00)×106/kg] in the second auto-HSCT, respectively. And the median time of platelet reconstruction was 12.0 d (9.0-17.0 d) in the first auto-HSCT and 14.0 d (9.0-18.0 d) in the second auto-HSCT, respectively. The median time of neutrophil reconstruction after transplantation was 12.0 d (9.0-16.0 d) in the first auto-HSCT and 13.0 d (9.0-16.0 d) in the second auto-HSCT, respectively. ② For all 48 patients, the overall response rate of DAHSCT was 93.8% (45/48) after receiving DAHSCT. The median follow-up time was 78.0 months (42.0-105.0 months). In this study, the rates of disease-free survival, recurrence and mortality were 64.6% (31/48), 16.7% (8/48) and 22.9% (11/48), respectively. ③ In this study, 5-year OS rate was 76.6% and 5-year progression-free survival (PFS) rate was 65.8%. ④ Results of univariate Cox regression analysis showed that achievement of complete remission (CR) before the second auto-HSCT was a protective influencing factor of OS period for aggressive NHL patients (HR=0.174, 95%CI: 0.051-0.598, P=0.005). And multivariate Cox regression analysis of factors that may influence the OS period of NHL patients showed that achievement of CR before the second auto-HSCT was an independent protective influencing factor of OS period for aggressive NHL patients (HR=5.046, 95%CI: 1.031-24.683, P=0.046). Conclusions DAHSCT treatment for aggressive NHL has good efficacy, especially for the patients with CR before the second auto-HSCT. However, whether DAHSCT deserves further clinical application in treatment of aggressive NHL patients still needs further study to confirm. Key words: Lymphoma, non-Hodgkin; Hematopoietic stem cell transplantation; Transplantation, autologous; Autologous hematopoietic stem cell transplantation

High-dose chemotherapy with autologous stem cell support for first-line treatment of aggressive non-Hodgkin lymphoma: a systematic review and meta-analysis based on individual patient data

Reason for withdrawal from publication The completion of the last task is overdue for more than one year. New authors are being sought to take over this protocol.

What are the effects of high-dose chemotherapy with autologous stem cell transplantation for the treatment of aggressive non-Hodgkin lymphoma?

What are the effects of high-dose chemotherapy with autologous stem cell transplantation for the treatment of aggressive non-Hodgkin lymphoma?

Genetic polymorphisms in oxidative stress‐related genes are associated with outcomes following treatment for aggressive B‐cell non‐Hodgkin lymphoma

Variable survival outcomes are seen following treatment for aggressive non-Hodgkin lymphoma (NHL). This study examined whether outcomes for aggressive B-cell NHL are associated with single nucleotide polymorphisms (SNPs) in oxidative stress-related genes, which can alter drug metabolism and immune responses. Genotypes for 53 SNPs in 29 genes were determined for 337 patients given anthracycline-based therapies. Their associations with progression-free survival (PFS) and overall survival (OS) were estimated by Cox proportional hazard regression; associations with hematologic toxicity were estimated by logistic regression. To validate the findings, the top three SNPs were tested in an independent cohort of 572 DLBCL patients. The top SNPs associated with PFS in the discovery cohort were the rare homozygotes for MPO rs2243828 (hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.14-3.06, P = 0.013), AKR1C3 rs10508293 (HR = 2.09, 95% CI = 1.28-3.41, P = 0.0032) and NCF4 rs1883112 (HR = 0.66, 95% CI = 0.43-1.02, P = 0.06). The association of the NCF4 SNP with PFS was replicated in the validation dataset (HR = 0.66, 95% CI = 0.44-1.01, P = 0.05) and the meta-analysis was significant (HR = 0.66, 95% CI = 0.49-0.89, P < 0.01). The association of the MPO SNP was attenuated in the validation dataset, while the meta-analysis remained significant (HR = 1.64, 95% CI = 1.12-2.41). These two SNPs showed similar trends with OS in the meta-analysis (for NCF4, HR = 0.72, 95% CI = 0.51-1.02, P = 0.07 and for MPO, HR = 2.06, 95% CI = 1.36-3.12, P < 0.01). In addition, patients with the rare homozygote of the NCF4 SNP had an increased risk of hematologic toxicity. We concluded that genetic variations in NCF4 may contribute to treatment outcomes for patients with aggressive NHL.

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.

Second Malignancies After Treatment of AIDS-Related Non-Hodgking's Lymphoma

Abstract 4943 Background:The use of highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of AIDS-related Non-Hodgkin lymphoma (NHL), causing a remarkable increase in patients' long-term survival. On the other hand, with the introduction of HAART, the incidence of non-AIDS-related malignancies is increasing among patients with HIV infection. The incidence of second neoplasms after treatment of aggressive NHL have been reported to be higher than in the general population. Nevertheless, there is scarce information regarding second malignancies occurring in HIV-infected patients after NHL treatment. We sought for second neoplasms among patients treated of AIDS-related NHL, hence suffering from 2 conditions which may predispose them to develop malignancies: therapy for lymphoma and HIV infection. Methods:We conducted a retrospective study of patient data on AIDS-related NHL individuals diagnosed between 1989 and 2010 in our institution. Demographic, HIV infection, and lymphoma data on each case were collected. Two groups were further considered: patients who did not take HAART at all, and those who started HAART at any stage of their HIV infection. Continuous and categorical variables are presented using descriptive statistics. Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. P-values of less than 0.05 were considered statistically significant. Results:Out of a series of 146 patients diagnosed with AIDS-related NHL, 138 patients were eligible for the study with a median follow-up of 8.24 years: 70 patients belonged to the no-HAART group, and 68 to the HAART group. Most interesting data regarding both groups are listed in table 1. Briefly, patients in the HAART group were older at the time of lymphoma diagnosis than those who did not receive it (p=0.024); in addition, there were more male patients in the no-HAART group (p=0.011). These differences show the demographic changes among HIV-infected patients in the HAART era. Furthermore, a higher number of complete responses (CR) to lymphoma treatment was observed in the HAART group (p<0.001). Overall survival (OS) and disease free survival (DFS) were significantly longer for patients who took HAART (p<0.001 and p<0.001 respectively).NAge mean (SD)Male genderTreated n (%)CT n (%)RT n (%)CR n (%)5-yr OS %2-yr DFS%Second neoplasm n (%)No HAART7037 (15)6244 (63)39 (56)6 (9)11 (16)2.918.20HAART6842 (10)4865 (95)64 (94)10 (15)40 (59)4979.54 (10%)Four out of the 40 patients at risk (10%), developed a second malignancy in the HAART group, and none in the no-HAART one. However, no statistically significant differences were found, probably due to the low number of cases. The most important features of the 4 patients with a second malignancy are listed in table 2. All 4 patients were diagnosed with diffuse large B-cell lymphoma (DLBCL), were treated with CHOP, and had a prior diagnosis of AIDS. Two of the 4 were on HAART at lymphoma diagnosis (one of them in both virological and immunological response). The patient with hepatocarcinoma was HCV positive. As shown in table 1, three of the patients had responded to HAART when the second neoplasm (carcinoma) was diagnosed; and the reminder, who did not respond to HAART, developed a Kaposi sarcoma. All four patients died because of neoplasm progression.Table 2PatientsAgeGenderHIV risk conditionHAART onsetTime to neoplasm (years)Type of NeoplasmHIV load (copies/mL)CD4/μL143MIVDUBefore NHL7.8Hepatocarcinoma0256240FSexualAfter NHL CT1.2Anal carcinoma0320357MSexualBefore NHL0.4Kaposi sarcoma32031941427FSexualConcomitant with NHL CT10.9Vaginal carcinoma0436 Conclusions:As expected, a higher frequence of second neoplasms was observed after treatment of AIDS-related NHL among patients who receive HAART. Second malignancies were non-HIV related neoplasms in patients with response to HAART.Abbreviations: CT, chemotherapy; RT, radiotherapy; IVDU: intravenous drug user. Disclosures:No relevant conflicts of interest to declare.

Pixantrone for the treatment of aggressive non-Hodgkin lymphoma

Importance of the field: At present there is no standard treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma who progress following second-line therapy. Anthracyclines are highly active drugs, but their use in this setting is limited by cumulative cardiac toxicity. Pixantrone is a new aza-anthracenedione structurally similar to mitoxantrone and anthracyclines. This compound has been developed to minimize cardiac toxicity without reducing efficacy.Areas covered in this review: This review summarizes the preclinical and clinical trial data for the use of pixantrone for the treatment of aggressive non-Hodgkin lymphoma.What the reader will gain: An overview of the mechanism of action of pixantrone, preclinical data, clinical efficacy, safety data and future developments for this compound.Take home message: Pixantrone has been shown to be superior to other single-agent therapies for the salvage treatment of relapsed/refractory aggressive non-Hodgkin lymphoma. The pixantrone application will be submitted to the regulatory authorities in the USA and in Europe.

R-CHOP vs. CHOP: A Cost-Effectiveness Analysis on Aggressive Non-Hodgkin's Lymphoma (NHL)

The CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) is the standard treatment for younger and elderly patients with diffuse large-B-cell lymphoma, but it induces complete responses in only 40 to 50 percent of elderly patients. The benefit of adding Rituximab (R) – a chimeric anti-CD20 IgG1 monoclonal antibody, to CHOP was observed among patients with relatively low risk disease or high risk disease. In comparative studies of CHOP and R-CHOP, the rate of complete response was significantly higher in the group that received R-CHOP than in the group that received CHOP alone. In several EU countries there are cost-effectiveness studies regarding the treatment of aggressive NHL with CHOP vs. R-CHOP, but in Romania there is no such a study done. The authors used a cost-effectiveness model where they compared the costs of both type of treatments and the benefits expressed in gained years of life, in order to have the Romanian perspective for the economic evaluation of treatment of aggressive NHL with CHOP vs. R-CHOP. The Romanian cost-effectiveness analysis is based on a model developed by Best et al. which calculates the cost-effectiveness ratio of R-CHOP vs. CHOP over time horizon of 10 years for patients with diffuse large B-cell lymphoma DLCL. The analysis was done based on local Romanian costs and the clinical benefits from the GELA study. Rituximab administered together with CHOP gives patients an increased chance of cure, a significantly superior survival and represents a cost-effective therapy compared to standard treatment with CHOP. When costs and survival benefits are considered over 10 years, the additional cost per patient on R-CHOP is 12,929 Euro. Over a 10 years time frame, the estimated survival benefit of R-CHOP compared to standard CHOP treatment alone in this group of patients is on average 0.60 extra years of life gained per patient. The estimated additional cost per extra year of life gained for the combination therapy is 21,549 Euro. Using the same cost-effectiveness model we observed that using R-CHOP vs. CHOP we obtained in Romania the lowest cost per additional year of life gained compared with France or United Kingdom. Keywords: cost-effectiveness analysis, cost per life year gained, NHL non-Hodgkin lymphoma

Recent developments in the treatment of aggressive non-Hodgkin lymphoma

Options for treating aggressive non-Hodgkin lymphoma (NHL) have expanded in recent years. In phase 3 clinical trials, giving rituximab with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) every 3 weeks (R-CHOP-21) has been associated with improved survival, without increased toxicity, in all patient groups studied. Giving dose-dense CHOP--CHOP every 2 weeks (CHOP-14)--has also proved appropriate for all patients 18-75 years old. Studies combining these approaches--dose-dense CHOP with rituximab (R-CHOP-14)--have shown improved survival over CHOP-14 in patients 60-81 years old. These results also indicate the importance of delivering chemotherapy at full dose and on schedule, which can improve survival in aggressive NHL. Effective delivery of dose-dense regimens requires granulocyte colony-stimulating factor support, which should also be considered for standard CHOP. A key question for the future is whether R-CHOP-14 is superior to R-CHOP-21.

High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive Non-Hodgkin Lymphoma (NHL) in adults

High-dose chemotherapy with autologous stem cell support (HDT) has been proven effective in relapsed aggressive non-Hodgkin lymphoma (NHL). However, conflicting results of HDT as part of first-line treatment have been reported in randomised controlled trials (RCTs). We undertook a systematic review and meta-analysis to assess the effects of such treatment. To determine whether high-dose chemotherapy with autologous stem cell transplantation as part of first-line treatment improves survival in patients with aggressive non-Hodgkin lymphoma. MEDLINE, EMBASE, Cancer Lit, the Cochrane Library and smaller databases, Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology were searched. We included full-text, abstract publications and unpublished data. Randomised controlled trials comparing conventional chemotherapy versus high-dose chemotherapy in the first-line treatment of adults with aggressive non-Hodgkin lymphoma were included in this review. Eligibility and quality assessment, data extraction and analysis were done in duplicate. All authors were contacted to obtain missing data and asked to provide individual patient data. Fifteen RCTs including 3079 patients were eligible for this meta-analysis. Overall treatment-related mortality was 6.0% in the HDT group and not significantly different compared to conventional chemotherapy (OR 1.33 [95% CI 0.91 to 1.93], P=0.14). 13 studies including 2018 patients showed significantly higher CR rates in the group receiving HDT (OR 1.32, [95% CI 1.09 to 1.59], P=0.004). However, HDT did not have an effect on OS, when compared to conventional chemotherapy. The pooled HR was 1.04 ([95% CI 0.91 to 1.18], P=0.58). There was no statistical heterogeneity among the trials. Sensitivity analyses underlined the robustness of these results. Subgroup analysis of prognostic groups according to IPI did not show any survival difference between HDT and controls in 12 trials (low and low-intermediate risk IPI: HR 1.41[95% CI 0.95 to 2.10], P=0.09; high-intermediate and high risk IPI: HR 0.97 [95% CI 0.83 to 1.13], P=0.71. Event-free survival (EFS) also showed no significant difference between HDT and CT (HR 0.93, [95% CI 0.81 to 1.07], P=0.31). Other possible risk factors such as the proportion of patient with diffuse large cell lymphoma, protocol adherence, HDT strategy, response status before HDT, conditioning regimens and methodological issues were analysed in sensitivity analyses. However, there was no evidence for an association between these factors and the results of our analyses. . Despite higher CR rates, there is no benefit for high-dose chemotherapy with stem cell transplantation as a first line treatment in patients with aggressive NHL.

Secondary Malignancies after Treatment of Aggressive Non-Hodgkin Lymphoma: A GISL Cohort Study on 1259 Patients.

BACKGROUND Secondary malignancies have been associated with Non Hodgkin Lymphoma (NHL) treatment. Nevertheless few analyses have addressed this issue focusing on aggressive lymphoma. Aims of this study were to determine the incidence and the risk factors for developing secondary cancer during long term follow up of patients treated for aggressive lymphoma.METHODS For the purpose of this study we identified in the GISL database, 1259 naïve patients with histologically confirmed diagnosis of aggressive NHL. Observed cancer were classified by site. The incidence numbers of second neoplasia was compared to the incidence of malignancies in the Italian population. The standardized incidence ratio was calculated from the ratio between observed and expected number of cancers. Absolute excess risk was calculated by subtracting the expected from the observed cases and dividing by the person-years at risk. The Time Free 2nd Tumour (TF2T) was measured from the end of the first treatment to last follow-up or date of diagnosis. Cumulative incidences were estimated either with a Kaplan-Meier estimate or by Gooley's method. Effects of potential risk factors on second cancer rates were examined in a Cox proportional-hazard model.RESULTS The cohort consisted of 1259 patients enrolled in GISL trials in the period 1988–2003, accounting for 6180 person-year at risk of second tumor. Median age at diagnosis was 58 years. All patients were treated with chemotherapy either alone or in combination with radiotherapy. During follow up, 44 patients (3.5%) developed a second cancer. Twelve out of 44 patients developed hematological malignancies and 32 solid tumors, including 7 lung cancer, 6 colorectal cancer, 4 prostate cancer and 15 other type of cancers. The median time for developing second tumors was 42 months. The risk of secondary malignancy overall was not increased. The analysis of risk by cohort of age at diagnosis of second cancer showed an excess of risk for the cohort age 20–39 and 40–59 years. Cumulative incidence of second malignancy, estimated by Kaplan Meier and by Gooley's method at 5, 10 and 15 years was 3.2%, 6.9% and 13.8%, and 2.7%, 5.2% and 9.6%, respectively. By univariate analysis we observed a significant negative impact on TF2T for age at first treatment and only marginally significant for elevated LDH level. Further, we performed a Cox regression analysis with gender, age at 1st treatment and LDH >UNL that showed the prognostic ability of these variables in predicting the risk of second tumour. We divided the log(HR) predicted from multivariate analysis, at the 33° and the 66° percentiles to obtain a score system. We observed three groups with significant difference (p< .0001) in the risk of developing second cancers.CONCLUSIONS Our results showed that the risk of second malignancy overall was not increased in patients treated for aggressive lymphoma. Cancer risk was age-related, as demonstrated by the excess of risk observed in the cohort age 20–39 and 40–59 years. Further, utilizing age, male gender and LDH in a Cox regression analysis, we demonstrated the prognostic value of these variables and we produced a score system able to identify groups with different risk of developing second malignancies.

Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma

AbstractCardiovascular disease frequently occurs after lymphoma therapy, but it is common in the general population too. Therefore, risk estimation requires comparison to population-based rates. We calculated risk by standardized incidence ratios (SIRs) and absolute excess risks (AERs) per 10 000 person-years based on general population rates (Continuous Morbidity Registry Nijmegen) in 476 (Dutch and Belgian) patients with aggressive non-Hodgkin lymphoma (NHL) treated with at least 6 cycles of doxorubicin-based chemotherapy in 4 European Organization for Research on Treatment of Cancer (EORTC) trials (1980-1999). Cumulative incidence of cardiovascular disease, estimated in a competing risk model, was 12% at 5 years and 22% at 10 years (median follow-up, 8.4 years). Risk of chronic heart failure appeared markedly increased (SIR, 5.4; 95% CI, 4.1-6.9) with an AER of 208 excess cases per 10 000 person-years, whereas risk of coronary artery disease matched the general population (SIR, 1.2; 95% CI, 0.8-1.8; AER, 8 per 10 000 person-years). Risk of stroke was raised (SIR, 1.8; 95% CI, 1.1-2.4; AER, 15 per 10 000 person-years), especially after additional radiotherapy (> 40 Gy). Preexisting hypertension, NHL at young age, and salvage treatment increased risk of all cardiovascular events; the effect of radiotherapy was dose dependent. In conclusion, patients are at long-term high risk of chronic heart failure after NHL treatment and need therefore life-long monitoring. In contrast, risk of coronary artery disease appeared more age dependent than treatment related.

New treatment strategies for aggressive lymphoma

For the past three decades chemotherapy with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) has been the standard treatment for aggressive non-Hodgkin's lymphoma (NHL), with only minor changes having been made to the regimen to increase its efficacy. Recently, however, clinical trials have shown significant improvements in outcome in aggressive NHL by showing the benefit of using dose-dense or accelerated schedules as well as by adding rituximab to the standard CHOP regimen. Maintaining the relative dose intensity (that is, delivering the full dose of the chemotherapy on schedule) is an important principle in achieving optimal outcomes in the treatment of NHL. Clinical studies have shown that dose reductions and delays result in poorer outcomes in patients with NHL, and in many cases greater dose intensity appears to result in greater overall and progression-free survival. In particular, compressing the delivery of the standard 21-day CHOP doses into a dose-dense 14-day schedule has been shown to increase event-free survival, overall survival, or both in patients with diffuse large B-cell lymphoma. Consequently, the CHOP-14 regimen (in which the dose intensity is 50% greater than that of the standard regimen) has been adopted by many oncologists for the treatment of aggressive NHL.

Serum-Soluble Tumor Necrosis Factor Receptor 2 (sTNF-R2) Level Determines Clinical Outcome in Patients with Aggressive Non-Hodgkin's Lymphoma.

The tumor necrosis factor (TNF) plays a key role in inflammatory processes, as this cytokine is one of the earliest to be produced in such a condition, and triggers the following cytokine cascade. In addition, the TNF and their receptor system are believed to play a key role in the growth, differentiation, and/or apoptosis of the malignant cells. As for TNF receptors, the two types, the 55 kDa (p55, TNFR; TNF-R1) and the 75 kDa (p75, TNFR; TNF-R2) are simultaneously expressed on many cells at different levels. The extracellular domains of these two receptors are released from the cell membrane by cleavage of TNF-Rs as soluble TNF-Rs (sTNF-R1, sTNF-R2). Reportedly the serum TNF-Rs level rise in patients with some malignancies. The aim of the present study was to assess the prognostic significance of serum sTNF-R in aggressive non-Hodgkin's lymphoma (NHL). Consecutive 110 previously untreated patients with aggressive NHL (diffuse large B-cell lymphoma; 94, peripheral T-cell lymphoma; 16) prospectively participated in this study between 1997 and 2002. The patients were treated with 6–8 cycles of CHOP or THP-COP regimens. To evaluate serum levels of sTNF-Rs (p55; TNF-R1, p75; TNF-R2), venous blood samples were drawn from patients immediately before the initiation of treatment. Serum sTNF-R1 and sTNF-R2 were determined using a sandwich enzyme-linked immunosorbent assay (ELISA). In healthy control subjects, the median of serum sTNF-R1 and sTNF-R2 levels were 1.2 ng/ml (range 0.3–2.9) and 4.17 ng/ml (range 1.91–8.51), respectively. High serum sTNF-R level was associated with some poor prognostic factors and low complete remission (CR) rate. Patients with high sTNF-R1(4 ng/ml and over) and sTNF-R2 (15 ng/ml and over) at onset had significantly lower survival rates (5-year: 19%, 19%) than those with low sTNF-R1 (under 4 ng/ml) and sTNF-R2 (under 15 ng/ml) (62%, 69%), respectively (p<0.0005, p<0.0001). Multivariate analysis employing sTNF-R2 and some conventional prognostic factors demonstrated that sTNF-R2 and performance status for overall survival (OS) and sTNF-R2, sIL-2R, and LDH for event free survival (EFS) were significantly poor prognostic factors. As for TNFa, a serum TNFa level is not related with sTNF-R1 or sTNF-R2 level in aggressive NHL. In addition, serum TNFa level is not associated with OS and EFS. In conclusion, serum sTNF-R2 might be a significant prognostic factor for aggressive NHL and a useful tool for selecting the appropriate therapeutic strategy in the treatment of aggressive NHL. The most reliable prognostic factor and the best combination of some prognostic factors for aggressive NHL should be clarified in order to assist in selecting appropriate treatment.

High-Dose Chemotherapy with Autologous Stem Cell Support Is Not Superior to Conventional-Dose Chemotherapy in the First-Line Treatment of Aggressive Non-Hodgkin Lymphoma - Results of a Comprehensive Meta-Analysis.

Background: High-dose chemotherapy with autologous stem cell support (HDT) has been proven effective in relapsed aggressive Non-Hodgkin lymphoma (NHL). However, conflicting results of HDT as part of first-line treatment have been reported in randomized controlled trials (RCTs). Here, we report our updated meta-analysis to better define the role of HDT in these patients.Methods: RCTs were identified by computerized search and handsearching of conference proceedings. Data extraction and quality assessment was performed independently by two reviewers. First authors were contacted to request individual patient data. Eight investigators provided us with individual patient data, for five trials data were extracted from survival curves. The hazard ratio (HR) was used as a measure of treatment effect; the inverse variance method (fixed effect model) was used for pooling. The relative risk was determined for binary data.Results: 15 RCTs including 3079 patients were eligible for this meta-analysis. Overall treatment-related mortality was 6.0% in the HDT group and not significantly different compared to conventional chemotherapy (RR 1.33, p=0.59). Analysis of 13 studies including 2018 patients showed significantly higher CR rates in the group receiving HDT (RR 1.10, p=0.004). However, HDT did not have an effect on OS, when compared to conventional chemotherapy. The pooled HR was 1.04 (p=0.58). There was no statistical heterogeneity among the trials and sensitivity analyses underscored the robustness of these results. Subgroup analysis of prognostic groups according to IPI did not show any survival difference between HDT and controls in 12 trials (low and low-intermediate risk IPI: HR 1.41, high-intermediate and high risk IPI: HR 0.97). Event-free survival (EFS) also showed no significant difference between HDT and CT (HR 0.93, p=0.31). We incorporated several additional variables to possibly identify other risk factors such as the proportions of diffuse large cell lymphoma, protocol adherence, the HDT strategy used, response status of patients before HDT, the conditioning regimen used, and methodological issues. However, our analyses demonstrate that the results described here are not related on either of these factors.Conclusion: Despite higher CR rates, there is no benefit for HDT in patients with aggressive NHL when incorporated in first-line treatment.

Phase II Study of Cyclophosphamide, Epirubicin, Vincristine, Prednisone, and Etoposide (CEOP-E) for Aggressive Non-Hodgkin's Lymphoma

The main objectives of the current study were to evaluate the efficacy and safety of a CEOP-E regimen for patients with aggressive non-Hodgkin's lymphoma (NHL). Fifty-one consecutive patients with newly diagnosed aggressive NHL were enrolled in the study. Median age of patients was 57 (range, 18-75) yr old, and male to female ratio was 1.32:1. Diffuse large B cell lymphoma (68.8%) was the most common histological subtype. Thirty patients (58.8%) had Ann Arbor stage III or IV diseases at diagnosis. One course of chemotherapy consisted of an intravenous combination of cyclophosphamide 750 mg/m2, epirubicin 50 mg/m2, vincristine 2 mg, etoposide 80 mg/m2 on day 1 and oral administration of 100 mg prednisone on days 1 to 5 (CEOP-E). A complete response or unconfirmed complete response was achieved in 31 (63.3%) out of 49 evaluated patients. With a median follow-up of 16.3 months, 26 events including relapse and death were observed. The estimated 2-yr survival rate for all patients and disease free survival rate for patients achieving complete re-sponse was 58.9% and 57.1%, respectively. Episodes of febrile neutropenia occurred in 5 (10.2%) patients. Transient episodes of ECG abnormality (1st degree AV block) were observed in 2 patients. Accordingly, the CEOP-E regimen produced comparable results to those of other regimens, including CHOP, in terms of the response rate and overall survival. The current regimen seemed to minimize the cardiac toxicity due to an accumulated dose of anthracycline in the treatment of aggressive NHL.

Effectiveness of Interferon-Alfa and Mid-Cycle Chemotherapy Added to an Anthracycline-Based Regimen in the Treatment of Aggressive Non-Hodgkin's Lymphoma

Interferon-alfa in combination with cytotoxic chemotherapy has been shown to be effective in treating certain types of non-Hodgkin's lymphoma (NHL) (1). However, there is no published data on upfront induction treatment of aggressive NHL with IFN-alfa containing regimens. Studies have also shown that one can overcome regrowth resistance by administering mid-cycle agents which slow tumor proliferation between courses of cytotoxic therapy (2). Based on this, we treated 32 consecutive patients between 1/93 and 9/96 with a regimen containing cyclophosphamide 750 mg/m2, mitoxantrone 12 mg/m2, and teniposide 60 mg/m2 IV on day 1 with prednisone 100 mg PO given on days 1–5. On day 15, patients received vincristine 1.4 mg/m2 (2 mg max.) and bleomycin 10 units/ m2 IV. Interferon-alfa-2b 5×l06 units/m2 SQ was administered on days 22–26. The median age was 55 (range 26–83), M:F ratio was 2.5:1, and the median International Prognostic Index was 2. 38% of patients had stages I-II and 62% had stages III-IV disease. Fifty-nine percent of the patients achieved a complete response, 22% a partial response, and 19% had progressive disease. The overall survival (OS) was 81% and the progression free survival (PFS) was 56% at 4.3 years. There were no severe (grade IV) hematologic, flu-like, GI and infectious toxicities from IFN-α. Leukopenia was the main severe toxicity related to the chemotherapy regimen (days 1–15), but not IFN-α. Severe infection secondary to the chemotherapy regimen occurred in one patient. Interferon-alfa-2b and mid-cycle chemotherapy added to an anthracycline based regimen is effective induction treatment for patients with aggressive NHL. The OS and PFS using this regimen, based on regrowth resistance, appears to be at least as or more effective than CHOP therapy for this group of patients. Severe toxicities were rare.