Raquel de Oña

Frontline treatment of follicular lymphoma with fludarabine, cyclophosphamide, and rituximab followed by rituximab maintenance: toxicities overcome its high antilymphoma effect. Results from a Spanish Cooperative Trial (LNHF-03)

We assessed the efficacy of fludarabine, cyclophosphamide, and rituximab in combination (FCR) as frontline treatment in patients with follicular lymphoma (FL) followed by rituximab maintenance. Seventy-five untreated patients with FL received FCR followed by maintenance with rituximab 375 mg/m2 weekly during 4 weeks and every 6 months for 2 years. The overall response rate was 100%, with 89% complete remission (CR) and 11% partial remission (PR). Molecular remission was observed in all but one patient. Only eight patients completed all therapy planned. With a median follow-up of 47 months, the 5-year overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were 77%, 93%, and 72%, respectively. Age below 60 and low Follicular Lymphoma International Prognostic Index (FLIPI) correlated with a better EFS. Ten patients died due to toxic complications. The FCR regimen is highly effective in untreated patients with FL, with 89% CR, including molecular responses, and a low progression rate. However, the high incidence of treatment-related mortality makes this regimen unsafe and it cannot be recommended as an upfront therapy in FL.

Evaluation of thrombophylic states in myeloma patients receiving thalidomide: a reasonable doubt

An increased incidence of deep venous thrombosis (DVT) has been described in multiple myeloma (MM). Its pathogenesis is multifactorial but the presence of other states of inherited or acquired thrombophilia can increase this hypercoagulability. Thalidomide has been used recently to treat refractory MM, and an increased risk of thrombosis has been reported when it is employed in combination with other chemotherapeutic agents (Zangari et al, 2001; Urbauer et al, 2002). We present a MM patient who was a homozygous carrier of the C677T mutation of the MTHFR gene who developed a DVT and a pulmonary embolism (PE) during thalidomide treatment. A 60-year-old man with stage IIIA Bence Jones MM was treated at diagnosis with conventional chemotherapy, and he achieved a complete response. During treatment, the patient suffered a DVT in the right subclavian vein associated with a central venous catheter. After disease relapse, thalidomide was initiated at 200 mg ⁄ d, in combination with 15-d cycles of dexamethasone. The thalidomide dose was increased by 200 mg ⁄ d every 2 weeks as tolerated. The patient reported constipation and drowsiness at the dose of 400 mg ⁄ d. At 800 mg ⁄ d, he had a slight polyneuropathy which disappeared when the dose was reduced to 600 mg ⁄ d. In the seventh month of treatment, the patient presented with progressive dyspnoea without other symptoms. On examination, the patient was obese, eupnoeic at rest and had normal cardiopulmonary examination. He had slight malleolar oedema without signs of DVT. Laboratory studies showed: haemoglobin 10Æ7 g ⁄ dl, and normal leucocyte count, platelet count, prothrombin time and activated partial thromboplastin time, and biochemically, fibrinogen 4Æ88 g ⁄ l, and proteinuria 700 mg ⁄24 h without evidence of Bence Jones protein. An arterial blood gas analysis showed hypoxaemia. D-dimer (by enzyme-linked immunosorbent assay) was 2428 ng ⁄ml (68–494 ng ⁄ml). The chest radiograph was normal and an electrocardiogram showed sinus tachycardia and repolarization disturbances. Pulmonary perfusion scintigraphy and helical computerized tomography were suggestive of PE. An echo-Doppler of the lower limbs detected a thrombosis in the right popliteal vein. Following the diagnosis of PE and DVT, anticoagulant treatment was initiated with good clinical results. A thrombophilia study indicated that he was homozygous for the C677T mutation of the MTHFR. High serum levels of homocysteine, 26 IU ⁄ml (normal < 15 IU ⁄ml), were also observed. Hyperhomocysteinaemia is associated with an increased risk of thrombosis. It is usually the result of acquired causes, although the MTHFR variant can contribute (Walker et al, 2001). Factor V Leiden and prothrombin G20201A, the most common genetic risk factors for thrombosis, were both negative. Other rare deficiencies of natural coagulation inhibitors, such as antithrombin III, protein S, protein C and plasminogen are detectable in less than 1% of the population. Our patient showed functional antithrombin III and plasminogen within the normal ranges. Acquired risk factors (antiphospholipid syndrome, oral contraceptives, major surgery) are also responsible for a large number of thrombotic events (Koster et al, 1993). The patient was negative for lupus anticoagulant and anticardiolipin antibodies. The patient had no family history of thrombosis. Thalidomide is an immunomodulator that inhibits the angiogenesis induced by vascular endothelial growth factor and fibroblast growth factor, although the exact mechanism of thalidomide in MM is unknown (Stirling, 2000). The percentage of DVT associated with treatment with thalidomide and chemotherapy including dexamethasone varies according to the series (4–28%) and a lower percentage of PE cases has been reported. This rate is greater than in MM patients not treated with thalidomide (Zangari et al, 2001; Zangari, 2002). A recent study indicates that a strong association exists between DVT and exposure to doxorubicin–thalidomide combination (Zangari et al, 2002). Nevertheless, no increase in the risk of thrombosis has been observed in MM treated with thalidomide as the only agent (2%). The thrombotic mechanism seems to be multifactorial in the DVT patients described. In our patient, the potential risk factors were MM, older age, obesity, relative immobility and genetic factors (MTHFR C677T homozygous with high levels of homocysteine), in addition to the treatment with thalidomide and dexamethasone. All cases of thrombosis described during the treatment with thalidomide have resolved favourably with anticoagulant treatment (Zangari et al, 2001; Urbauer et al, 2002), as in our patient. For this reason, the development of thrombosis is not an absolute contraindication for continuing treatment. Patients with a personal and family history of thrombosis must be investigated for genetic and acquired prothrombotic factors before they begin thalidomide treatment. Therefore, prophylactic anticoagulation should be considered in selected patients. British Journal of Haematology, 2003, 122, 159–167

Validation of the NCCN-IPI for diffuse large B-cell lymphoma (DLBCL): the addition of β2 -microglobulin yields a more accurate GELTAMO-IPI.

The study included 1848 diffuse large B‐cell lymphoma (DLBCL)patients treated with chemotherapy/rituximab. The aims were to validate the National Comprehensive Cancer Network International Prognostic Index (NCCN‐IPI) and explore the effect of adding high Beta‐2 microglobulin (β2M), primary extranodal presentation and intense treatment to the NCCN‐IPI variables in order to develop an improved index. Comparing survival curves, NCCN‐IPI discriminated better than IPI, separating four risk groups with 5‐year overall survival rates of 93%, 83%, 67% and 49%, but failing to identify a true high‐risk population. For the second aim the series was split into training and validation cohorts: in the former the multivariate model identified age, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, Stage III‐IV, and β2M as independently significant, whereas the NCCN‐IPI‐selected extranodal sites, primary extranodal presentation and intense treatments were not. These results were confirmed in the validation cohort. The Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO)‐IPI developed here, with 7 points, significantly separated four risk groups (0, 1–3, 4 or ≥5 points) with 11%, 58%, 17% and 14% of patients, and 5‐year overall survival rates of 93%, 79%, 66% and 39%, respectively. In the comparison GELTAMO IPI discriminated better than the NCCN‐IPI. In conclusion, GELTAMO‐IPI is more accurate than the NCCN‐IPI and has statistical and practical advantages in that the better discrimination identifies an authentic high‐risk group and is not influenced by primary extranodal presentation or treatments of different intensity.

Clinical experience of bendamustine treatment for non-Hodgkin lymphoma and chronic lymphocytic leukemia in Spain

Bendamustine is a alkylating agent with a purine-like benzamidazole ring currently approved in Europe for indolent non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma. Our aim was to analyze retrospectively the efficacy and toxicity of bendamustine in NHL and CLL in Spain in the bendamustine Compassionate Use Program. Patients with relapsed/refractory NHL or CLL were eligible. Any regimen containing bendamustine was eligible. 109 patients were included from 22 institutions. Forty-nine patients had indolent NHL, 18 aggressive NHL and 42 CLL, being 44 patients (40%) refractory to previous treatment. 63% of patients had adverse events grade 3-4, mainly hematological. Overall response rate (ORR) was 66%, complete responses 30%. ORR observed in refractory patients was 45%. The median progression-free survival (PFS) was 13 months. Outcome was influenced by histology, number of previous treatments, resistance to previous chemotherapy and type of response achieved with bendamustine. Alone or in combination, bendamustine shows a meaningful clinical antitumor activity in patients with relapsed or refractory NHL or CLL, with an acceptable toxicity profile.

Relationship between deoxycytidine kinase (DCK) genotypic variants and fludarabine toxicity in patients with follicular lymphoma.

DCK catalyzes the intracellular phosphorylation of fludarabine. The promoter and coding region of the DCK gene were analyzed in 74 follicular lymphoma (FL) patients receiving a therapeutic regimen that included fludarabine. DCK mRNA expression was quantified in a cohort of healthy donors. Four previously described genotypic variants, -360C>G, -201C>T (rs2306744), C28624T (rs11544786) and c.91+37G>C (rs9997790), as well as the new variant, -12C>G, were identified. Variant C28624T showed a lower risk of lymphopenia (P=0.04), but a higher risk of neutropenia (P=0.04). Statistical significance was found in bivariate logistic regression between lymphopenia and infectious episodes in the induction period (odds ratio 3.85, P=0.04).

Evaluation of Clinical and Biological Prognostic Factors in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Patients After Previous Treatment With Rituximab and Chemotherapy: Results of the PRO-R-IPI Study

INTRODUCTION Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, showing a highly variable outcome. In patients with DLBCL relapsed/refractory to first-line treatment with rituximab the usefulness of the revised International Prognostic Index (R-IPI) as a prognostic tool remains unexplored. Some biological parameters (B-cell lymphoma 6 [Bcl-6], Bcl-2, p53, and multiple myeloma 1 [MUM1]) and blood populations (lymphocyte and monocyte counts) have been described as International Prognostic Index-independent prognostic factors. The objective was to evaluate the R-IPI to predict the outcome of DLBCL patients at the time of relapse after a front-line treatment with chemotherapy and rituximab and to establish in this population the relationship between biological parameters and outcome. PATIENTS AND METHODS We included patients with refractory/relapsed DLBCL after first-line treatment with rituximab-containing regimens; patients must have already finished a rescue treatment also including rituximab. Immunohistochemical assessment of Bcl-2, Bcl-6, p53, and MUM1 expression were undertaken in available biopsies. R-IPI factors were identified from the clinical data at diagnosis and at relapse. Response was assessed using National Cancer Institute-sponsored Working Group guidelines. RESULTS R-IPI prognosis at relapse was not significantly associated with overall response rate (ORR) after Rituximab-chemotherapy rescue therapy. None of the immunohistochemical parameters analyzed correlated with rescue therapy results. In contrast, patients with absolute lymphocyte count (ALC) ≥ 1 × 10(9)/L at relapse were more likely to respond than patients with ALC < 1 × 10(9)/L (P = .05). CONCLUSION The R-IPI score calculated at relapse could not predict the ORR to second-line treatment. Lymphopenia is a simple and useful predictor for outcome in relapsed/refractory DLBCL and the only prognostic factor that in our hands could predict the overall response to a second-line treatment with rituximab and chemotherapy.

Differential prognostic impact of GELTAMO-IPI in cell of origin subtypes of Diffuse Large B Cell Lymphoma as defined by the Hans algorithm

The Grupo Español de Linfomas y Trasplantes de Médula Ósea International Prognostic Index (GELTAMO‐IPI) stratifies four risk groups in diffuse large B cell lymphoma (DLBCL) patients treated with immunochaemotherapy: low (LR), low‐intermediate (LIR), high‐intermediate (HIR), and high (HR). The present study explores the effect of GELTAMO‐IPI in the DLBCL subtypes defined by the immunohistochaemistry‐based Hans algorithm, Germinal Centre B (GCB) and non‐GCB. A multivariate Cox regression model including GELTAMO‐IPI risk groups, cell of origin (COO) subtypes and their product was developed to evaluate interaction between the two variables. The COO subtype was available in 839 patients (380 GCB; 459 non‐GCB) and both the GELTAMO‐IPI and the COO subtype in 780 (353 GCB; 427 non‐GCB). There were no differences in 5‐year overall survival (OS) between the two subtypes. The Cox model revealed interaction between the GELTAMO‐IPI risk groups and the COO subtypes (P = 0·005), indicating that GELTAMO‐IPI has a different effect in the two subtypes. Three risk groups were stratified in both COO subtypes: in the GCB subtype, LR, LIR and the combined HIR+HR had 5‐year OS of 100%, 75% and 52%, respectively. In the non‐GCB subtype, LR, the combined LIR+HIR and HR had a 5‐year OS of, 97%, 82% and 35% respectively. GELTAMO‐IPI identifies a genuine poor outcome group of patients in the DLBCL non‐GCB subtype.