Cyclophosphamide , Vincristine And Prednisolone Research Articles

Effectiveness and Adverse Events of Cyclophosphamide, Vincristine, and Prednisolone Chemotherapy in Feline Mediastinal Lymphoma Naturally Infected with Feline Leukemia Virus.

Simple SummaryFeline leukemia virus (FeLV) infection is considered a poor prognostic factor for feline lymphoma. Cyclophosphamide, vincristine and prednisolone (COP) chemotherapy is a standard protocol treatment of feline lymphoma. This retrospective study involved 92 cats diagnosed with mediastinal or mediastinal plus other anatomical sites of lymphoma and treated with COP chemotherapy. Clinical signs and adverse events were observed after the 1st, 2nd, and 3rd inductions. Clinical signs improved after the 3rd induction of COP chemotherapy. The response rate was 96.74%. The overall median survival time was 338 days (range 62–1057 days). This study found that cats aged <4 years had longer survival than those aged at least 4 years. Anemia (before COP), azotemia (after 2nd induction) and elevated alanine aminotransferase (after 1st induction) was associated with an increased chance of mortality.Feline leukemia virus (FeLV) infection is considered a poor prognostic factor for feline lymphoma. This study investigated the prevalence of cats suffering from feline lymphoma with natural infection of the feline leukemia virus, as well as clinical signs, adverse events, and survival time after cyclophosphamide, vincristine and prednisolone (COP) chemotherapy. This retrospective study involved 92 cats diagnosed with mediastinal or mediastinal plus other anatomical sites of lymphoma and treated with COP chemotherapy. FeLV-antigen-positive was observed in all cats. Clinical signs and adverse events were observed after the 1st, 2nd, and 3rd inductions. Clinical signs improved after the 3rd induction of COP chemotherapy. The response rate was 96.74% (81.52% complete response, 15.22% partial response, and 3.26% no response). The overall median survival time was 338 days (range 62–1057 days). The overall response rate and median survival time of cats with feline lymphoma that were FeLV-antigen-positive and treated with COP chemotherapy were higher than from other studies. This study found that cats aged <4 years survived longer than those aged at least 4 years. Anemia (before COP), azotemia (after 2nd induction), and elevated alanine aminotransferase (after 1st induction) were associated with an increased chance of mortality.

Results of Inter-B-NHL Ritux 2010 - Phase II Study of DA-EPOCH-R for Children and Adolescents with Primary Mediastinal Large B-Cell Lymphoma (PMLBL) on Behalf of European Intergroup for Childhood Non Hodgkin's Lymphoma (EICNHL) and Children's Oncology Group (COG)

BackgroundDose Adjusted EPOCH with Rituximab (DA-EPOCH-R) has been shown to deliver excellent survival for adults with PMLBL (Dunleavy K et al. NEJM 2013; 368:1408-16). We evaluated this regimen in a prospective international trial of children and adolescents with this disease.MethodsThe international phase II trial (NCT01516567) sponsored by Gustave Roussy and COG, evaluated the event-free-survival (EFS) following DA-EPOCH-R in patients with PMLBL aged <18 years. A total of 6 courses of DA-EPOCH-R with escalation of doses as in published literature were delivered. A course of cyclophosphamide, vincristine and prednisolone (COP) was allowed 1 week prior to commencement of DA-EPOCH-R for urgent treatment whilst awaiting histological confirmation. The primary endpoint was EFS with events as presence of viable cells in residue after 6th course, progression, relapse, second malignancy or death from any cause. The efficacy of DA-EPOCH-R was assessed by comparing the observed EFS with that of the historical rate modeled by [S(t) = 0.67 + 0.33{exp(-1.5t)}] (t in years), using the one-sample log-rank test. The planned sample size was 40 patients.ResultsBetween April 2012 and April 2016, 47 eligible patients (35 from Europe and 12 from COG) were recruited across 7 countries. Twenty-seven were female and the median age was 15 years. Thirty-two percent of patients had lactate dehydrogenase (LDH)> 2xNormal, 66% had mediastinal mass >10cm and 16% were Stage IV by Ann Arbor classification. Pathological review is ongoing (15/47 cases already reviewed). Due to a protocol error 7 patients received only half dose predniso(lo)ne in DA-EPOCH-R and on the recommendation of the Independent Data Monitoring Committee the additional 7 patients were recruited. The primary analysis was restricted to the 40 patients treated according to the full predniso(lo)ne dosing. Sensitivity analyses were conducted on the whole group of 47 patients. The median follow up was 27 months (range 9.9- 53 months)Forty percent of patients (17/47) received a COP prior to the first course of DA-EPOCH-R. The protocol was well tolerated and 47% (22/47) of patients reached dose level 4 or higher. Febrile neutropenia was seen in 11% (30/281) of courses. One patient experienced left ventricular systolic dysfunction (grade 2) at dose level 6.Eighty-five percent (39/46) of patients achieved complete remission (CR) or CR (unconfirmed). There were 13 events (11 relapse/refractory or progression and 2 second malignancies). Isolated CNS relapse occurred in 2 patients. The observed 2-year EFS among the 40 patients who received full dose prednisolone of 69% (95%CI 52%-82%) did not differ from the historical rate (p=0.71). A similar result was seen in the sensitivity analysis of all 47 patients (EFS 72% (95% CI 57%-84%), p=0.68). The 2-year overall survival rate for all 47 patients was 82% (95%CI 67-91%). An analysis of prognostic factors for the whole group showed that the presence of extrathoracic involvement was associated with associated with inferior outcome in multivariate analysis (HR 5.62[1.49-21.2], p=0.011).ConclusionDA-EPOCH-R did not improve the EFS compared to a historical control in this international study of children and adolescents with PMLBL in contrast to the published adult series. Further studies are required to determine the optimum therapy for children and adolescents with this lymphoma. DisclosuresBollard:Cellectis: Membership on an entity's Board of Directors or advisory committees; Neximmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Torque: Membership on an entity's Board of Directors or advisory committees.

Treatment Outcome and Prognostic Model for Stage IE/IIE Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Retrospective Study in a Cohort of 305 Patients with Long Term Follow-up

BackgroundExtranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a rare and distinct subtype of non-hodgkin lymphoma (NHL). The frequency was higher in Asia than in western countries and it has become the most common subtype of peripheral T-cell lymphomas in China. The majority of ENKL patients present with early stage. Optimal treatment modalities and prognostic factors for localized ENKL have not been fully defined. This study aimed to evaluate the optimal treatment strategy and prognostic factors for localized ENKL patients.MethodsBetween 2003 and 2013, three hundred and five patients with stage IE/IIE ENKL were comprehensively analyzed in this study. A total of 180 patients received combined chemoradiotherapy, with 111 patients received radiotherapy alone and 14 patients recieved chemotherapy alone. Chemotherapy regimens include GDP (gemcitabine, cisplatin, and dexamethasone), CHOP (epirubicin, cyclophosphamide, vincristine, and prednisolone) and other regimens. A total dose of 50 Gy to the primary tumor was considered as radical dose for ENKL, and additional 5 to 10 Gy was administered as a boost to the residual disease.ResultsThe complete response (CR) rate for patients received chemoradiotherapy (n=175) was significantly higher than that for patients received radiotherapy alone (n=102) (89.1 % vs.77.5 %, P = 0.009) or chemotherapy alone (n=14) (89.1 % vs.21.4 %, P< 0.001). The median follow up time for all 305 patients was 38.7 (1.1 to 393) months. For 228 stage IE paranasal extension or IIE patients, 3-year overall survival (OS) in combined chemoradiotherapy (n=154), radiotherapy alone (n=60) and chemotherapy alone (n=14) groups were 85.7%, 73.3% and 57.1% respectively (chemoradiotherapy vs. radiotherapy, P =0.003; chemoradiotherapy vs. chemotherapy, P<0.001). For patients received combined chemoradiotherapy, GDP regimen (n=54) (included 10 patients with pegaspargase) could significantly improve 3-year progression-free survival (PFS) compared with CHOP-like (n=110) (included 10 patients with asparaginase) (88.9% vs. 70.9%, P =0.015).Patients received radiotherapy first followed by chemotherapy (n=84) was associated with superior 3-year PFS compared with patients initially received chemotherapy (n=96) (81.0% vs. 69.8%, P =0.034). But for 54 patients received GDP regimen, induction chemotherapy (n=17) could increase 3-year PFS (100.0% vs. 83.8%, P =0.112) and OS (100.0% vs. 86.5%, P =0.180). We identified 3 risk groups based on 3 prognostic factors (stage II, LDH elevated and paranasal extension) with different survival outcomes. The 3-year OS rates were 93.5%, 85.0% and 62.2% respectively for patients with no risk factors, 1 or 2 factors and 3 factors (P<0.001).ConclusionsCombined chemoradiotherapy is the most optimal therapy strategy for stage IE paranasal extension or IIE ENKL patients. GDP or combined with pegaspargase regimen shows promising efficacy, significant superior to the traditional CHOP regimen. The sequence of chemotherapy and radiotherapy for patients received novel chemotherapy regimens still needs further assessment in phase 3 clinical trials. We identified 3 risk groups based on 3 prognostic factors (stage II, LDH elevated and paranasal extension) with different survival outcomes and this novel prognostic model may better predict prognosis than previous International Prognostic Index (IPI) and Korean Prognostic Index (KPI) score for ENKL patients with limited stage. DisclosuresNo relevant conflicts of interest to declare.

PCN187 - Treatment Patterns of Indolent Non-Hodgkin Lymphoma Patients Under the Brazilian Public Health Care Perspective

To identify the chemotherapeutic treatment patterns in patients with indolent non-hodgkin lymphoma (NHL) treated in the Brazilian Public Healthcare System. A retrospective longitudinal analysis based on the Government administrative claims database (Datasus) was performed from January 2008 to December 2012. Eligibility criteria were patients with indolent NHL diagnosed until January 2012 and starting their first chemotherapy regimen from January 2008 to January 2012. This cohort of patients was followed until December 2012, death or loss of follow-up. Patients without interruption during treatment and without change in medication were considered in the same chemotherapy regimen. Descriptive statistics (average, standard deviation and percentage) of treatment regimens, treatment free interval (TFI), age at the beginning of treatment, gender and length of treatment were performed. A total of 817 patients with indolent NHL representing 5,449 APACs (Authorization for High Complexity Procedures) met eligibility criteria. The population cohort comprised 50.7% men with an average age of 61.3±14.5years. 72.2% of the patients had only one chemotherapy regimen, whereas 18.2% had two and 9.1% had three or more chemotherapy regimens. Time between diagnose and the beginning of treatment was 3.6±6.2 months. The most widely used first chemotherapy regimen was cyclophosphamide, vincristine and prednisolone (CVP)(22.2%) followed by cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) and rituximab(15.7%), cyclophosphamide, vincristine and prednisolone (COP) and rituximab(5.6%), chlorambucil and prednisone(4.8%). Average length of treatment was 5.0±3.7months. For second chemotherapy scheme, the most widely used regimen was CHOP and rituximab(14.1%), CVP(7.5%), interferon(9.3%), chlorambucil and prednisone(6.2%). The average length of treatment was 4.0±4.1months, with an average TFI of 3.3±4.2months. The most used chemotherapy in first regimen was CVP. Rituximab in combinations was present in most patients in the first scheme. Rituximab in second scheme in combination with CHOP was the most used therapy. The length of treatment was longer in first scheme.

PCN184 - Treatment Patterns of Chronic Lymphocytic Leukemia Patients Under the Brazilian Public Health Care Perspective

To identify the chemotherapeutic treatment patterns in patients with chronic lymphocytic leukemia (CLL) treated in the Brazilian Public Healthcare System. A retrospective longitudinal analysis based on Government administrative claims database (Datasus) was performed from January 2008 to December 2012. Eligibility criteria were patients with CLL (ICD code C911) diagnosed until January 2012 and starting their first chemotherapy regimen from January 2008 to January 2012. This cohort of patients was followed until December 2012, death or loss of follow-up. Patients without interruption during treatment and without change in medication were considered in the same chemotherapy regimen. Descriptive statistics (average, standard deviation and percentage) of treatment regimens, treatment free interval (TFI), age at treatment start, gender and length of treatment were performed. A total of 1,538 patients with CLL representing 15,371 APACs (Authorization for High Complexity Procedures) met eligibility criteria. The population cohort comprised 56.6% men with an average age of 67.4±12.1 years. 55.0% of the patients had only one chemotherapy regimen, whereas 44.9% had two and 19.4% had three or more chemotherapy regimens. Time between diagnosis and beginning of treatment was 4.3±7.6 months. The most widely used first chemotherapy regimen was chlorambucil (54.9%), followed by cyclophosphamide, vincristine and prednisolone (CVP) (9.1%), fludarabine and cyclophosfamide (FC) (8.1%) and chlorambucil and prednisone (7.0%). Average length of treatment was 6.3±5.7 months. For second chemotherapy scheme, the most widely used regimen was chlorambucil (45.3%), followed by FC (11.0%), CVP (7.8%), chlorambucil and prednisone (6.2%) and CHOP (3.5%). The average length of treatment was 4.9±3.6 months, with an average TFI of 3.5±5.0 months. Chlorambucil was the most used therapy as both first and second chemotherapy regimen. There was a decreasing of Chlorambucil and an increasing of FC in second scheme. The length of treatment was longer in first scheme.

Rituximab for the first-line treatment of stage III–IV follicular lymphoma (review of Technology Appraisal No. 110): a systematic review and economic evaluation.

Follicular lymphoma (FL) is a non-Hodgkin's lymphoma which typically presents when the disease is at an advanced stage. The majority of patients receive first-line therapy of rituximab in combination with chemotherapy, with two-thirds receiving cyclophosphamide, vincristine and prednisolone. The clinical and cost-effectiveness of other chemotherapies in combination with rituximab in first-line therapy is not known. To systematically evaluate and appraise the clinical effectiveness and cost-effectiveness of rituximab (MabThera(®), Roche Products) in combination with chemotherapy, compared with chemotherapy alone, for the first-line treatment of symptomatic stage III-IV FL. A systematic review of literature and an economic evaluation were carried out. Key databases [including MEDLINE In-Process & Other Non-Indexed Citations; Cumulative Index to Nursing and Allied Health Literature (CINAHL); EMBASE; The Cochrane Library, including the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED) and Health Technology Assessment (HTA) databases; Science Citation Index (SCI); and BIOSIS], plus research registers and conference proceedings, were searched for relevant studies from inception up to October 2010. One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. The quality of included studies was assessed by one reviewer and checked by a second. A patient-level simulation model was developed to estimate the costs and quality-adjusted life-year (QALY) gains from the perspective of the UK NHS and Personal Social Services, with costs and benefits discounted at 3.5% annually. Four randomised controlled trials comparing rituximab plus chemotherapy (R-chemotherapy) with chemotherapy alone in untreated, symptomatic patients with stage III-IV FL were identified. R-chemotherapy compared with chemotherapy alone increased the likelihood of a response to treatment in all four trials, with no additional toxicity of clinical relevance. Overall response rates were significantly improved in all four trials, with a difference between the R-chemotherapy and chemotherapy arms of between 5% and 24%, respectively. Complete response rates were also improved, with a difference between the R-chemotherapy and chemotherapy arms of between 2% and 25%, respectively. Exploratory meta-analyses were conducted; the level of statistical heterogeneity was very high and thus we believe the response rates from the individual trials to be a more robust estimator of the efficacy of the specific R-chemotherapy regimens. Over a follow-up period of 4-5 years, R-chemotherapy significantly increased the overall survival rate compared with chemotherapy alone in three trials, although data for two trials were compromised owing to the use of additional treatments. The incremental cost-effectiveness ratio (ICER) for the addition of rituximab to CVP (cyclophosphamide, vincristine and prednisolone), CHOP (cyclophosphamide, doxorubicin/adriamycin, vincristine and prednisolone) and MCP [mitoxantrone, chlorambucil (Leukeran(®), Aspen) and prednisolone] was £7720, £10,834 and £9316 per QALY gained, respectively, when it was assumed that first-line rituximab maintenance was not used. A scenario analysis is also presented, assuming that responders to R-chemotherapy in first-line induction receive maintenance with rituximab, increasing the ICER to £14,959, £21,687 and £20,493 per QALY gained, respectively. These relate to the sources of data used for the effectiveness in first and second line and the assumed utility values; there is uncertainty about the effect of salvage treatment on patients who had been previously treated with an anthracycline regimen. There is uncertainty whether or not rituximab is as effective in second-line treatment when patients have been previously treated with rituximab. The results from four randomised trials comparing R-chemotherapy with chemotherapy alone showed an improvement in clinical effectiveness outcomes, with minimal clinically relevant additional adverse events or toxicity. The cost per QALY gained is estimated to be < £25,000 for all three comparisons under our base-case assumption and is considerably lower if first-line rituximab maintenance is not assumed. More data on patients pre-treated with rituximab and on the effect of first-line maintenance with rituximab is required for future work. The National Institute for Health Research Health Technology Assessment programme.

FDG‐PET guided diagnosis of vaginal intravascular diffuse large B‐cell lymphoma

A 76-year-old woman presented with a 6-month history of progressive bilateral lower limb weakness, anorexia and weight loss and the recent onset of urinary and faecal incontinence with saddle anaesthesia. There was no palpable lymphadenopathy. Urgent magnetic resonance imaging (MRI) ruled out spinal cord or cauda equina compressive lesions. Blood tests showed a raised lactate dehydrogenase (LDH) and erythrocyte sedimentation rate with an IgM paraprotein of 7 g/l; immunoglobulins were otherwise normal. Cerebrospinal fluid analysis showed a reactive lymphocytosis on morphology and by flow cytometry. Bilateral bone marrow aspirates and trephine biopsies were normal. Computed tomography (CT) was entirely normal but a repeat MRI with gadolinium showed enhancement of lumbosacral nerve roots suggestive of infiltrative disease. [F]fluorodeoxyglucose (FDG) positron emission tomography (PET) showed diffuse uptake in the uterus, cervix, vagina and numerous groups of lymph nodes throughout the body. The FDG-PET findings led to a vaginal mucosal biopsy, which showed subepithelial capillaries packed with neoplastic lymphoid cells (left) expressing CD20 (right), CD79a and CD5 with a Ki-67 index of 100%; the histological features were those of intravascular diffuse large B-cell lymphoma (DLBCL). At the time of diagnosis the patient had a performance score of 4 and she remained an inpatient. She received twice weekly intrathecal methotrexate, followed by one cycle of CVP (cyclophosphamide, vincristine and prednisolone combination chemotherapy). Rituximab was given 1 week later due to the high risk of tumour lysis syndrome, which has been reported previously. Unfortunately she developed neutropenic sepsis and died 2 weeks after diagnosis. Despite extensive prior investigations it was the results of the FDG-PET scan that eventually guided the biopsy site. The lack of solid lesions makes routine CT and MRI unhelpful in diagnosing this rare subtype of extranodal DLBCL; approximately 50% of patients are diagnosed at autopsy. This case highlights how the nonspecific and diverse symptoms, in the absence of significant lymphadenopathy, can result in critical delays in diagnosing this clinically aggressive lymphoma and how the use of FDG-PET scanning in such patients can guide the biopsy site.

SIL index, comprising stage, soluble interleukin-2 receptor, and lactate dehydrogenase, is a useful prognostic predictor in diffuse large B-cell lymphoma.

Rituximab (R) plus doxorubicin, cyclophosphamide, vincristine, and prednisolone (CHOP) chemotherapy (R-CHOP) is widely accepted as standard care for diffuse large B-cell lymphoma (DLBCL) patients. The revised International Prognostic Index (R-IPI) was established in 2007 after the addition of rituximab to standard DLBCL treatment. To reassess the utility of R-IPI, we carried out a retrospective analysis of patients with DLBCL uniformly treated with standard R-CHOP. Progression-free survival (PFS) curves in "very good" and "good" risk groups as defined by the R-IPI showed no statistical difference. We added soluble interleukin-2 receptor (sIL-2R) level to the factors comprising the R-IPI. Five levels of sIL-2R were weighed with respect to their impact on PFS. sIL-2R of >2500 U/mL was determined as the most appropriate threshold. We developed a new prognostic SIL index, which includes three independent prognostic risk factors: clinical stage (S); sIL-2R level over 2500 U/mL (I); and elevated lactate dehydrogenase level (L). This index indicates standard risk (0 or 1 risk factors, 4-year PFS 83%, 4-year overall survival 91%) and high risk (2 or 3 risk factors, 4-year PFS 52%, 4-year overall survival 67%) outcomes. The SIL index is a simple and objective prognostic index for DLBCL patients to identify candidates for experimental therapy other than R-CHOP.

Angioimmunoblastic T-cell lymphoma: the effect of initial treatment and microvascular density in 31 patients

The objectives of this study are to explore the clinical features and treatment outcomes and to investigate the correlation between microvessel density (MVD) and survival in patients with angioimmunoblastic T-cell lymphoma (AITL). We retrospectively analyzed clinical and follow-up data of 31 patients treated in two hospitals during 1995-2009 histologically proven AITL. We also assessed MVD in the lump of 31 previously untreated patients using α-CD34 immunohistochemical staining. The median age of the 31 patients was 48 years, eighty percent of the patients were in an advanced stage. 67.7% of them had B symptoms, with the follow-up of 2-13 years, the 5-year overall survival rate was 25.8%. The response rates (RR) of CHOP group and COP (cyclophosphamide, vincristine and prednisolone) group are 76.5 and 75%, respectively, which is no significant difference (P=0.894). RR did not differ whether chemotherapy regimens contained anthracycline or not. The 3-year PFS rate for patients who received COP and CHOP regimen was 25.4 and 35.3% (P=0.562), while 5-year OS rates were 25.0 and 29.4%, respectively (P=0.667). The median PFS for patients with high MVD and low MVD were 15.1 and 30.0 months (P=0.048), while the median OS were 20 and 45 months, respectively (P=0.038). Patients who were sensitive to initial chemotherapy COP regimen have the similar therapeutic effect to CHOP regimen. Patients with high MVD measured in the microenvironment had worse PFS and OS than AITL patients with low expression.

Primary cardiac lymphoma mimicking atrial thrombus in a patient who underwent permanent pacemaker implantation

Dear Editor, Primary cardiac lymphoma is a rare malignant lymphoma of the heart and pericardium [1, 2]. Delayed diagnosis is an ominous prognostic factor because of the non-specific initial presentation and rapid progression of this disease [3–7]. An 82-year-old woman with atrial fibrillation was prescribed amiodarone since early June 2009. In July 2009, she experienced dizziness, palpitation, and exertional dyspnea. Electrocardiography (ECG) revealed atrial fibrillation with slow ventricular rate (30–40/min). Amiodarone-induced arrhythmia was suspected initially, and then amiodarone was discontinued for more than 3 weeks. However, she continued experiencing dizziness occasionally and electrocardiography revealed junctional bradycardia. The patient was admitted to our cardiovascular ward. Holter ECG revealed a prolonged sinus pause (>3 s). Echocardiography showed left atrial dilatation (Fig. 1a). A permanent pacemaker was implanted via the left subclavian vein. Five days later, echocardiography (transthoracic and transesophageal) revealed a mass-like lesion, which was not observed 2 months earlier, in the right atrial appendage (Fig. 1b). The lesion was suggestive of a thrombus that was associated with pacemaker implantation. The patient was prescribed anticoagulants and thrombolytic agents. However, a series of echocardiographies performed during the treatment period revealed poor response. After 4 weeks, computed tomography (Fig. 1c) revealed a filling defect in the heart and bilateral pleural effusion. To investigate the cause of the intracardiac mass, we performed an operation in September 2009. Subtotal removal of the masses was performed because total resection was impossible. Pathologic examination revealed (Fig. 1d) large B cell lymphoma. Bone marrow examination showed no invasion of the lymphoma cells. Positron emission tomography revealed a diffuse linear pattern of fluorodeoxyglucose (F-FDG) uptake in the cardiac recess; FDG uptake was not observed in any other region. Physical examination did not reveal palpable lymphadenopathy or other mass lesions. The patient refused further treatment after the operation. However, she developed progressive orthopnea and exertional dyspnea in early October 2009. Follow-up echocardiography revealed enlargement of the heart mass. The patient received a series of systemic chemotherapy, including one cycle of COP (cyclophosphamide, vincristine, and prednisolone) followed by seven cycles of R-CHOP (rituximab, cyclophosphamide, anthracycline, vincristine, and prednisolone) until April 2010. The latest echocardiS.-F. Cho : S.-F. Lin Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin’s lymphoma

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin's lymphoma (FNHL) based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's scope restricts the intervention to rituximab in combination with CVP (cyclophosphamide, vincristine and prednisolone) (R-CVP); the only comparator used was CVP alone. The evidence from the one included randomised controlled trial (RCT) suggests that the addition of rituximab to a CVP chemotherapy regimen has a positive effect on the outcomes of time to treatment failure, disease progression, overall tumour response, duration of response and time to new lymphoma treatment in patients with stage III/IV FNHL compared with CVP alone. Adverse events were comparable between the two arms. This study was confirmed as the only relevant RCT. The economic analyses provided by the manufacturer were modelled using a three-state Markov model with with the health states being defined as progression-free survival (PFS), progressed (in which patients have relapsed) and death (which is an absorbing state). The model generated results for a cohort of patients with an initial age of 53 and makes no distinction between men and women. The model is basic in design, with several serious design flaws and key parameter values that are probably incompatible. Attempting to rectify the identified errors and limitations of the model did not increase the incremental cost-effectiveness ratio (ICER) above 30,000 pounds. Although the cost-effectiveness results obtained appear to be compelling in support of R-CVP compared with CVP for the trial population the results may not be so convincing for a more representative population. The results of the ERG analysis on the impact of age suggest that ICERs increase steadily with age, as the proportion of PFS that can be converted to overall survival (OS) is diminished by rising mortality rates in the general population. For the most extreme scenario (no OS gain) the ICER appears to remain below 30,000 pounds per QALY gained. On balance the evidence indicates that R-CVP is more cost-effective than CVP. The guidance issued by NICE in July 2006 as a result of the STA states that rituximab within its licensed indication (in combination with cyclophosphamide, vincristine and prednisolone) is recommended as an option for the treatment of symptomatic stage III/IV follicular non-Hodgkin's lymphoma in previously untreated patients.

Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin’s lymphoma

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin’s lymphoma (FNHL) based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer’s scope restricts the intervention to rituximab in combination with CVP (cyclophosphamide, vincristine and prednisolone) (R-CVP); the only comparator used was CVP alone. The evidence from the one included randomised controlled trial (RCT) suggests that the addition of rituximab to a CVP chemotherapy regimen has a positive effect on the outcomes of time to treatment failure, disease progression, overall tumour response, duration of response and time to new lymphoma treatment in patients with stage III/IV FNHL compared with CVP alone. Adverse events were comparable between the two arms. This study was confirmed as the only relevant RCT. The economic analyses provided by the manufacturer were modelled using a three-state Markov model with with the health states being defined as progression-free survival (PFS), progressed (in which patients have relapsed) and death (which is an absorbing state). The model generated results for a cohort of patients with an initial age of 53 and makes no distinction between men and women. The model is basic in design, with several serious design flaws and key parameter values that are probably incompatible. Attempting to rectify the identified errors and limitations of the model did not increase the incremental cost-effectiveness ratio (ICER) above £30,000. Although the cost-effectiveness results obtained appear to be compelling in support of R-CVP compared with CVP for the trial population the results may not be so convincing for a more representative population. The results of the ERG analysis on the impact of age suggest that ICERs increase steadily with age, as the proportion of PFS that can be converted to overall survival (OS) is diminished by rising mortality rates in the general population. For the most extreme scenario (no OS gain) the ICER appears to remain below £30,000 per QALY gained. On balance the evidence indicates that R-CVP is more cost-effective than CVP. The guidance issued by NICE in July 2006 as a result of the STA states that rituximab within its licensed indication (in combination with cyclophosphamide, vincristine and prednisolone) is recommended as an option for the treatment of symptomatic stage III/IV follicular non-Hodgkin’s lymphoma in previously untreated patients.

Economic evaluation of rituximab plus cyclophosphamide, vincristine and prednisolone for advanced follicular lymphoma

The addition of rituximab to cyclophosphamide, vincristine and prednisolone (CVP) for advanced follicular lymphoma increases median time to progression by 17 months. A US societal cost-effectiveness of R-CVP versus CVP is estimated for a representative 50-year-old patient. Progression-free survival (PFS) and overall survival are based on a randomized Phase III trial. Costs are estimated using Medicare reimbursement rates and published drug price data, and include drug and administration costs, adverse events, treatment of relapses, and end-of-life care. Utility estimates are derived from the literature and a 3% discount rate is employed. Mean overall survival is projected to be 1.51 years longer for patients assigned to R-CVP versus CVP. The cost per quality-adjusted year of life gained is $28,565. The utility associated with stable or progressive disease and the unit drug cost of rituximab most influence the findings. The cost-effectiveness ratio of R-CVP compared with CVP is projected to be cost-effective in the United States under a range of sensitivity analyses.

The cost–effectiveness of rituximab in non-Hodgkin’s lymphoma

Rituximab was the first available genetically engineered monoclonal antibody that targets CD20 proteins on the surface of B-cells. Rituximab is indicated: as the first-line treatment of diffuse-large B-cell non-Hodgkin’s lymphoma (NHL) in combination with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); as the first-line treatment of stage III–IV follicular NHL in combination with cyclophosphamide, vincristine and prednisolone (CVP); for the treatment of patients with stage III–IV follicular lymphoma who are chemoresistant or in their second or subsequent relapse after chemotherapy; and as maintenance therapy for patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without rituximab. This article reviews the published economic evaluations of rituximab in the treatment of NHL. The conclusion of these analyses is that rituximab, used both as monotherapy and in combination with chemotherapy, is a cost-effective intervention in the most common forms of NHL, diffuse large B-cell lymphoma and follicular NHL. However, there exists a paucity of published studies on both the clinical and economic analysis of rituximab in the less common NHLs. Currently, rituximab is being evaluated in clinical trials within other NHLs. If it has the same clinical success in these trials as it has had in diffuse large B-cell lymphoma and follicular lymphoma, then it is possible that within a few years rituximab could play a key role in treating patients in all forms of NHL.

AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy

We aimed to compare AIDS risk-adapted intensive chemotherapy in AIDS-related lymphoma (ARL) patients before and after the advent of highly active antiretroviral therapy (HAART). A total of 485 patients aged from 18 to 67 years were randomly assigned to chemotherapy after stratification according to an HIV score based on performance status, prior AIDS, and CD4(+) cell counts below 0.10 x 10(9)/L (100/mm(3)). A total of 218 good-risk patients (HIV score 0) received ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisolone) or CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisolone); 177 intermediate-risk patients (HIV score 1), CHOP or low-dose CHOP (Ld-CHOP); and 90 poor-risk patients (HIV score 2-3), Ld-CHOP or VS (vincristine and steroid). The 5-year overall survival (OS) in the good-risk group was 51% for ACVBP versus 47% for CHOP (P = .85); in the intermediate-risk group, 28% for CHOP versus 24% for Ld-CHOP (P = .19); and in the poor-risk group, 11% for Ld-CHOP versus 3% for VS (P = .14). The time-dependent Cox model demonstrated that the only significant factors for OS were HAART (relative risk [RR] 1.6, P < .001), HIV score (RR 1.7, P < .001), and the International Prognostic Index (IPI) score (RR 1.5, P < .001) but not chemotherapy regimen. Our findings indicate that in ARL patients, HIV score, IPI score, and HAART affect survival but not the intensity of the CHOP-based chemotherapy.

A Case of Primary Hepatic B-cell Lymphoma of Mucosa-associated Lymphoid Tissue (MALT)-Type

Mucosa-associated lymphoid tissue (MALT) lymphoma is a low grade B cell lymphoma that, occurs in numerous sites including the stomach, ocular adnexa, thyroid, lung and breast; however, primary hepatic lymphoma is extremely rare. Only about 20 cases have been reported world wide. We recently experienced a case of primary hepatic B-cell lymphoma of the MALT type in a 63-year old female patient. She presented with abdominal pain. The CT, ultrasonogram and PET-CT showed a hepatic nodular mass. A biopsy specimen of the liver revealed MALT lymphoma. There was no evidence of the lymphoma in the extrahepatic lesion. She received segmentectomy of liver and was then treated with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy. She has been followed up for 6 months since the therapy, and she remains asymptomatic.

Pharmacokinetic interaction between chemotherapy for non-Hodgkin's lymphoma and protease inhibitors in HIV-1-infected patients

We have investigated whether chemotherapy for HIV-related systemic non-Hodgkin's lymphoma (NHL) affects the pharmacokinetics of protease inhibitors. This was a prospective, open-label, non-randomized, two-way crossover trial in HIV-1-infected patients treated with highly active antiretroviral therapy and chemotherapy for NHL. Seven patients received indinavir at a dosage of 800 mg three times daily and three patients received nelfinavir at a dosage of 750 mg three times daily. Chemotherapy consisted of adriamycin, cyclophosphamide, vincristine and prednisolone (CHOP). Each patient had blood samples for protease inhibitor pharmacokinetics drawn concomitantly with or independently of the CHOP cycle. When indinavir was given concomitantly with CHOP, the AUC(0-8) increased by 38% (20.5 +/- 9.0 versus 14.9 +/- 9.5 mg.h/L; P=0.03), and was comparable to historical controls. By contrast, the AUC(0-8) of indinavir administered without CHOP was lower than expected. A similar trend was observed with nelfinavir. Likewise, we observed a significant number of patients with C(0) and C(8) below the IC(50) for the wild-type virus (0.1 mg/L) when the drug was administered without CHOP. Therapeutic drug monitoring of protease inhibitors should be part of the work-up in HIV-infected patients receiving chemotherapy for NHL.

Long-term Results of a Multicenter Randomized, Comparative Trial of Modified CHOP versus THP-COP versus THP-COPE Regimens in Elderly Patients with Non-Hodgkin's Lymphoma

In treating elderly non-Hodgkin's lymphoma (NHL) patients, it is particularly important to use drugs that have a low incidence of adverse events and high efficacy. In this multicenter study, THP (pirarubicin)-COP (cyclophosphamide, vincristine, and prednisolone) was compared to two thirds dosage of full CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen with regard to both adverse events and efficacy. For a third group, etoposide (E) was added to the THP-COP regimen (THP-COPE) in order to achieve high dose-intensity. Subjects were 486 previously untreated patients, aged 65 or older (range, 65-92 years; median, 74 years), with NHL. Subjects were randomly assigned to receive THP-COP, two thirds CHOP, or THP-COPE. Four hundred and forty-three patients were assessed for response and followed for 8 years after the last subject registered. The complete remission rates for the THP-COP, CHOP, and THP-COPE groups were 42.5%, 41.4%, and 48.0%, respectively. There was no difference in overall survival or progression-free survival among these 3 groups. In aggressive lymphoma, there was also no difference in complete response (CR) rate (45.3% in THP-COP, 44.9% in CHOP, 48.0% in THP-COPE), overall survival, and progression-free survival among these groups. The 5- and 8-year survival rates for all patients were 29.4% and 18.7%, respectively. The 5- and 8-year survival rates for patients with aggressive lymphoma were 27.4% and 17.4%, respectively. Although long-term survival for patients with aggressive lymphoma on our regimens was not worse compared to previous reports, the CR rate was lower. Because severe adverse events were not observed, higher dose chemotherapy may be directed to achieve better CR rates. In patients with T-cell-type lymphoma, the CR rate was greater after treatment with THP-COP (51.4%) or THP-COPE (57.7%) compared to treatment with CHOP (19.4%). Pirarubicin may be more useful for T-cell lymphoma than doxorubicin. Because adverse cardiac events were reported only in CHOP, adverse cardiac events might be low in the THP group.

Radiation Therapy for Leukaemic Involvement of Maxillary Sinus in Chronic Lymphatic Leukaemia

Sir – We would like to report a rare case of chronic lymphocytic leukaemia (CLL) with isolated leukaemic deposits in maxillary sinus. Its excellent response to local radiotherapy is discussed. A 50-year-old man presented with complaints of tiredness and generalised weakness. Clinically, the patient was pale and had multiple palpable left-sided neck nodes and hepatosplenomagaly. Other body systems were essentially normal on clinical examination. On haematological examination, haemoglobin was 6 gm%, total leukocyte count was 53 600/mm 3 and the peripheral lymphocytes were positive for CD5 and CD19 antigens. Ultrasonography of the abdomen confirmed hepatosplenomegaly apart from revealing para-aortic, ceoliac and mesenteric lymphadenopathy, with minimal ascitis and bilateral pleural effusion. Bone-marrow examination confirmed the diagnosis of CLL, Rai stage IV. He was started on induction combination chemotherapy with cyclophosphamide, vincristine and prednisolone (CVP). After three cycles of chemotherapy, although his total leukocyte count decreased and neck nodes regressed, hepatosplenomegaly, ascites and pleural effusion increased. He was, therefore, considered for a combination of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). On completion of three cycles of chemotherapy, he showed marked improvement in hepatosplenomegaly, ascitis and pleural effusion, but developed progressive swelling of the left side of his face, with malar prominence, proptosis and periorbital puffiness. Magnetic resonance imaging showed a mass in the left maxillary sinus invading the floor of orbit and extending into infra-temporal fossa (Fig. 1). Fine-needle aspiration cytology confirmed it to be a leukaemic infiltrate. Radiotherapy was delivered to left maxillary sinus mass by anterior and lateral-wedged portals up to a dose of 15 Gy in 6 fractions in 1 week. A prompt response was observed, and the facial swelling and proptosis disappeared completely by the end of radiotherapy. After radiotherapy, he was started on fludarabine but his disease progressed rapidly and he finally succumbed after 3 months. However, until his death, the patient was completely asymptomatic at the local site of radiation. Extralymphatic involvement is common in acute leukaemias but infrequent and asymptomatic in chronic leukaemia. However, leukaemic-cell infiltrates may become symptomatic depending on their location. Involvement of scalp, subconjunctiva, prostate, gonads, pharynx, lungs, gastrointestinal tract, pericardium, central nervous system and kidney are known [1]. Leukaemic infiltration in the maxillary sinus in CLL has not been reported previously to the best of our knowledge. It has been documented in acute nonlymphoblastic leukaemias that leukaemic deposits may be resistant to systemic chemotherapy and 25% of patients require local radiation or surgery for its management [2]. Thus, local radiotherapy to a total dose of 500–1500 cGy in 5–15 fractions has been advocated with success [3]. The present case, with an unusual leukaemic deposit in maxillary sinus that was chemoresistant, demonstrated a complete regression and stable resopnse with 15 Gy of local radiation.

L-Asparaginase-Based Induction Therapy for Advanced Extranodal NK/T-Cell Lymphoma

We describe treatment of a patient with advanced extranodal NK/T-cell lymphoma, nasal type, with multiple subcutaneous lesions and hemophagocytic syndrome. Considering the projected poor outcome of conventional treatments, we designed an L-asparaginase-based induction therapy. L-asparaginase (4000 units/day, day 1 to day 7) combined with vincristine (1 mg, day 1) and prednisolone (100 mg/day, day 1 to day 5) was administered by intravenous infusion every 3 weeks. Within a week after treatment was started, excellent response was observed. Because of an allergic reaction to L-asparaginase, 6 courses of CHOP (adriamycin, cyclophosphamide, vincristine and prednisolone) therapy were administered as consolidation after 4 courses of L-asparaginase. The lymphoma was controlled with complete remission lasting longer than 2 years without additional treatment. These results and related reports may contribute to greater therapeutic efficacy against at least some cases of extranodal NK/T-cell lymphoma and other related diseases. Further evaluations based on clinical study are expected to clarify these results.