Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma

BACKGROUND: The current study was conducted to asses the safety profile and clinical activity of rituximab in combination with fludarabine and cyclophosphamide in patients with recurrent follicular lymphoma (FL). METHODS: This study was a noncomparative, multicenter, phase II study. Between March 2000 and December 2002, 54 patients with recurrent FL were enrolled in the FC+R trial. Patients received fludarabine at a dose of 25 mg/m(2) and cyclophosphamide at a dose of 300 mg/m(2) daily for 3 consecutive days, every 3 weeks for 4 cycles. Rituximab was administered at a dose of 375 mg/m(2) beginning 2 weeks after the first course of fludarabine and cyclophosphamide and then on Day 1 of each cycle thereafter. The planned treatment duration was 10 weeks. RESULTS: Overall, 92% of patients completed the planned therapy in 10 to 14 weeks and 74% achieved a complete response (CR). Among patients with BCL2-positive bone marrow, 86% obtained a molecular disease remission (MR). The median survival from treatment (SFT), the duration of disease remission (DR), and time to disease progression (TTP) had not been reached after a median follow-up of 45 months. Of the baseline characteristics, >2 previous treatments, BCL2-positive bone marrow, and low Follicular Lymphoma International Prognostic Index (FLIPI) score were found to be associated with better DR and/or TTP. Hematologic toxicity was transient and reversible, with the exception of 3 patients with severe and prolonged neutropenia. Three patients presented with infections, 1 of whom died of bronchopneumonia. CONCLUSIONS: The FC+R scheme, a nonanthracycline-containing regimen lasting up to 10 weeks, was found to be relatively well-tolerated and demonstrated significant antilymphoma activity with excellent clinical CR and molecular response rates.     

Two autologous transplants in the treatment of patients with Hodgkin's lymphoma: analysis of prognostic factors and comparison with a single procedure

We summarized registry data of the long term observation of 35 patients treated with two autologous transplants. Prognostic factors for overall survival (OS) and DFS were analyzed. The OS was compared with 105 patients from a single transplant group. Two factors were significant in univariate analysis of DFS after the second transplant: response to the first transplant (complete remission (CR) versus progressive disease (PD) p = 0.041) and the disease status at the time of the second autologous stem cell transplantation (ASCT) (CR versus partial remission (PR) p = 0.004; CR versus PD p = 0.0002). In the multivariate analysis only the last of the parameters remain significant (RR 2.30, p = 0.004, 95% CI; 1.30 - 4.04). In the analysis of OS, two factors were significant in univariate analysis: status of the disease at the first transplant (PR versus PD p = 0.008) and response to the first transplant (CR versus PD p = 0.025). None of those factors remained significant in a multivariate analysis. A probability of 5-year survival after the first transplant in patients treated with two transplants was 83% (95% CI; 70 - 97%). A tendency towards better survival was seen in patients treated with two transplants (p = 0.01). The trend toward better survival from the time of diagnosis is kept for those who entered CR or PR after standard chemotherapy (p = 0.097) but not for the whole group (p = 0.13).     

Phase II study of chemotherapy and stem cell transplantation for adult acute lymphoblastic leukemia or lymphoblastic lymphoma: Japan Clinical Oncology Group Study 9004

Granulocyte colony-stimulating factor (G-CSF)-supported, post-remission chemotherapy (Cx) for adult acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) was evaluated. One hundred and forty-three eligible patients (median age, 41 years) including 126 ALL and 17 LBL receiving induction Cx (vincristine, cyclophosphamide, prednisolone [PSL], doxorubicin, L-asparaginase, intrathecal-methotrexate [IT-MTX]) were analyzed. For patients achieving complete response (CR), two courses of post-remission Cx (course A of daunorubicin, cytosine arabinoside, vindesine, PSL plus IT-MTX; course B of mitoxantrone, etoposide, vincristine, PSL plus IT-MTX) with the use of G-CSF were repeated alternately; thereafter, maintenance Cx including MTX and 6-mercaptopurine was given for 2 years. One hundred and nineteen (83%) patients achieved CR, while 14 (10%) died during induction. Among the 119 patients achieving CR, five died in remission, 76 relapsed, and the remaining 38 were alive without disease. The median survival time of the 143 eligible patients was 26 months (95% confidence interval, 19-34). At a median follow-up time of 9 years, the 5-year survival rate was 32% and the 5-year progression-free survival (PFS) rate was 26%. The 5-year survival rate of 36 patients who underwent autologous (n = 20) or allogeneic stem cell transplantation (SCT; n = 16) in the first CR group was 58%. Compared with the authors' previous trials, survival and PFS were markedly improved. In conclusion, G-CSF-supported, intensive post-remission Cx and subsequent SCT are worthy of further investigation for the treatment of adult ALL and LBL.     

Chromosome instability and translocation t(11;18) in primary gastric marginal zone B-cell lymphoma of MALT-type

The prognosis for patients with mucosa-associated lymphoid tissue (MALT) lymphomas is good; these tumours have usually an indolent course with overall survival rates that are greater than 80% at 5-year, but some rare cases with histological transformation in aggressive diffuse large cell lymphoma have also been diagnosed. Here, we present cytogenetic results on endoscopic bioptic material of 42 cases of primary gastric extranodal marginal zone B-cell lymphoma (EMZL) using fluorescence in situ hybridization (FISH) approach with API2, MALT1 and centromeric probes for chromosome 3 and 18, and their impact on the clinical outcome.     

Tumour-associated macrophages in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group

Wada N, Zaki M A A, Hori Y, Hashimoto K, Tsukaguchi M, Tatsumi Y, Ishikawa J, Tominaga N, Sakoda H, Take H, Tsudo M, Kuwayama M, Morii E & Aozasa K
(2012) Histopathology  60, 313–319
Tumour‐associated macrophages in diffuse large B‐cell lymphoma: a study of the Osaka Lymphoma Study Group Aims: To evaluate the role of tumour‐associated macrophages (TAMs) of the M1 and M2 types in the behaviour of diffuse large B‐cell lymphoma (DLBCL). Methods and results: Double immunohistochemical staining of HLA‐DR/CD68 (M1) or CD163/CD68 (M2) was performed in 101 cases of DLBCL. CD68+ cells represent the total number of TAMs. The average number of double‐positive cells was counted, and the cut‐off value was set at the mean number of counts, i.e. 30.7 and 27.0 for M1 TAMs and M2 TAMs, respectively. That for total TAMs was set at the 90th percentile number of total counts, i.e. 132.3. Cases were categorized into three pairs: high (34 cases) and low (67 cases) M1 TAM groups, high (39 cases) and low (62 cases) M2 TAM groups, and high (10 cases) and low (91 cases) total TAM groups. The difference in overall survival rates was statistically significant between the high and low M2 TAM groups (P < 0.01) and between the high and low total TAM groups (P < 0.05). Multivariate analysis revealed that the presence of a bulky mass and a higher number of M2 TAMs were significant factors for poor prognosis (P < 0.05). Conclusions: Estimation of specific type of macrophages, of the M1 and M2 types, is superior to the estimation of TAMs as a whole (CD68+ cells) for prediction of the prognosis of DLBCL patients.     

European multi-centre study on coeliac disease and non-Hodgkin lymphoma

INTRODUCTION: Coeliac disease (CD) is associated with an increased risk of non-Hodgkin lymphoma (NHL), but there is little information about whether this is true for clinically silent CD. OBJECTIVE: To investigate the frequency of CD in two European populations; one with NHL and another derived from the general population. METHODS: A prospective, multi-centre, case-control study in 10 European countries was conducted between May 1998 and April 2001. A total of 1446 consecutive patients with newly diagnosed NHL aged over 18 years was collected. The control group consisted of a population of 9676 individuals who were screened for CD. The number of patients with a previous diagnosis of CD and those with silent CD detected by screening were determined in the two groups. RESULTS: The patients with CD had a significantly increased risk of developing NHL [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.9]. This risk was only present in patients with CD diagnosed clinically before the study (OR 3.3, 95% CI 1.4-7.9), but not in those with silent CD detected by screening (OR 1.3, 95% CI 0.6-2.7). CONCLUSION: Patients with CD have an increased risk of developing NHL, although this is lower than previously thought. Clinically silent CD is rare in patients with NHL.     

Molecular follow-up in gastric mucosa-associated lymphoid tissue lymphomas: early analysis of the LY03 cooperative trial

Gastric marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)-type can regress after anti-Helicobacter pylori treatment. The International Extranodal Lymphoma Study Group, the United Kingdom Lymphoma Group, and the Groupe d'Etude des Lymphomes de l'Adulte have conducted a trial to ascertain whether the addition of chlorambucil is of benefit after anti-H pylori therapy. At the last interim analysis, 105 (55%) of 189 patients had achieved a complete histologic remission after anti-Helicobacter therapy. To further assess the ability of treatment to eradicate the lymphoma clone, we analyzed the gastric biopsies from a subset of the patients by polymerase chain reaction (PCR) targeted to the immunoglobulin heavy chain genes as a molecular marker for minimal residual disease. Sixty-two cases were examined at diagnosis. Fifty-four cases were monoclonal by PCR. Forty-two of these patients achieved histologic complete remission (hCR) after anti-Helicobacter treatment: 34 cases underwent molecular follow-up analysis. Fifteen patients (44%) were in molecular remission with a median follow-up of 2 years after antibiotic treatment and of 1 year after the achievement of hCR. Less than half of the patients with MALT lymphoma can achieve sustained molecular remission after anti-Helicobacter therapy. The presence of molecular disease in the absence of histologic disease does not appear to be associated with histologic relapse, but, given the indolent nature of MALT lymphomas, a longer follow-up is needed.     

Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group

Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R + high-dose cytarabine. Responders received high-dose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progression-free survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.