A randomized phase II study comparing consolidation with a single dose of 90Y ibritumomab tiuxetan vs. maintenance with rituximab for two years in patients with newly diagnosed follicular lymphoma responding to R-CHOP. Long-term follow-up results.

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to 90Y-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m2 every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving 90Y-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.

Chronic lymphocytic leukemia with isochromosome 17q: An aggressive subgroup associated with TP53 mutations and complex karyotypes.

Although i(17q) [i(17q)] is frequently detected in hematological malignancies, few studies have assessed its clinical role in chronic lymphocytic leukemia (CLL). We recruited a cohort of 22 CLL patients with i(17q) and described their biological characteristics, mutational status of the genes TP53 and IGHV and genomic complexity. Furthermore, we analyzed the impact of the type of cytogenetic anomaly bearing the TP53 defect on the outcome of CLL patients and compared the progression-free survival (PFS) and overall survival (OS) of i(17q) cases with those of a group of 38 CLL patients harboring other 17p aberrations. We detected IGHV somatic hypermutation in all assessed patients, and TP53 mutations were observed in 71.4% of the cases. Patients with i(17q) were more commonly associated with complex karyotypes (CK) and tended to have a poorer OS than patients with other anomalies affecting 17p13 (median OS, 44 vs 120 months, P = 0.084). Regarding chromosomal alterations, significant differences in the median OS were found among groups (P = 0.044). In conclusion, our findings provide new insights regarding i(17q) in CLL and show a subgroup with adverse prognostic features.

Long-term safety and outcome of fludarabine, cyclophosphamide and mitoxantrone (FCM) regimen in previously untreated patients with advanced follicular lymphoma: 12 years follow-up of a phase 2 trial.

Fludarabine combinations are very affective in follicular lymphoma (FL) with high rates of complete response and prolonged survival. However, late toxicities could be a concern. The aim of the present study was to analyze the long-term impact on survival, relapse and late toxicities of a trial of treatment with fludarabine, mitoxantrone and cyclophosphamide (FCM regimen) for untreated patients with advanced stage FL. One hundred and twenty patients enrolled in a phase 2 trial of treatment with FCM regimen between 2000 and 2003 were evaluated. After a median follow-up of 12 years, 52 patients eventually relapsed/progressed with 10 year progression-free survival (PFS) of 46 %. Ten patients showed histological transformation to aggressive lymphoma with a risk of transformation of 2 and 9 % at 5 and 10 years, respectively. Three patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and seven solid neoplasms with an overall risk of 3 and 8 % at 5 and 10 years, respectively. Twenty-six patients eventually died during the follow-up. Overall survival at 10 years was 83 %. In conclusion, FCM regimen allows excellent long-lasting response in previously untreated patients with FL. The incidence of late events including histological transformation and secondary neoplasia is low but not negligible.

Long-Term Follow-Up of a Phase II Trial of Six Cycles of Dose-Dense R-CHOP-14 for First-Line Treatment of Diffuse Large B-Cell Lymphoma in Young and Elderly Patients.

BACKGROUND/AIMS: Rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 14 days seems to achieve better outcomes than R-CHOP every 21 days in diffuse large B-cell lymphoma (DLBCL) patients. Currently, the standard regimen is R-CHOP every 21 days. METHODS: This is a phase II clinical trial of treatment with 6 cycles of R-CHOP-14 with pegfilgrastim support in 2 populations of previously untreated DLBCL patients aged ≥65 years (n = 73) or <65 years (n = 51) with low-risk International Prognostic Index scores (0-2). RESULTS: With a median follow-up of 63.7 months, the 5-year event-free survival rate was 53.8% in patients aged ≥65 years and 71.0% in patients aged <65 years. The 5-year overall survival rate was 71.4 and 89.8%, respectively. The complete remission rate was 69.9% for older and 80.4% for younger patients. The median relative dose intensity of cytotoxic drugs was 143.2% in the elderly and 149.1% in the young patients. Febrile neutropenia was the most common grade 3-4 adverse event, being higher in elderly patients (21.3 vs. 9.3%). Eight deaths (7 in elderly patients) were considered treatment related. CONCLUSION: In conclusion, the R-CHOP-14 regimen is feasible and very active, though it is more toxic in elderly patients mainly due to an increased incidence of infections. New strategies, such as new monoclonal antibodies or new targeted therapies, are needed to improve the outcomes of DLBCL patients.

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.

Donor CTLA-4 genotype influences clinical outcome after T cell-depleted allogeneic hematopoietic stem cell transplantation from HLA-identical sibling donors.

CTLA-4 (cytotoxic T-lymphocyte antigen-4) plays a pivotal role in inhibiting T cell activation through competitive interaction with B7 molecules and interruption of costimulatory signals mediated by CD28. Polymorphisms on the CTLA-4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with graft-versus-host disease (GVHD) or relapse after allogeneic transplant. As CTLA-4 is expressed on T-lymphocytes, the aim of this study was to determine whether the donor CTLA-4 CT60 genotype also influences clinical outcome even after T cell depletion with CD34-positive selection. We studied 136 patient-donor pairs. Overall survival (OS) was worse for those patients who received grafts from a donor with the CT60 AA genotype rather than from a donor with the AG or GG genotype (35.6% vs 49.4%; P = .043). This association was confirmed through multivariate analysis, which identified the donor CT60 genotype as an independent risk factor for OS (P = .008; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.23-4.08). The donor CT60 AA genotype was also associated with lower disease-free survival, this being related to an increased risk of relapse (P = .001; HR: 3.41, 95% CI: 1.67-6.96) and a trend toward higher transplant-related mortality. These associations were stronger when considering only patients in the early stage of disease. Our results suggest that graft-versus-leukemia (GVL) activity after T cell depletion is conditioned by the donor CTLA-4 genotype.

Benefit from autologous stem cell transplantation in primary refractory myeloma? Different outcomes in progressive versus stable disease.

BACKGROUND: Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. DESIGN AND METHODS: In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (≥ 25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. RESULTS: There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). CONCLUSIONS: Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease.

[Non-pegylated liposomal doxorubicin in combination with cyclophosphamide, vincristine, prednisone and rituximab for the treatment of non-Hodgkin's lymphoma: study of 26 patients]. / Doxorrubicina liposomal no pegilada en combinación con ciclofosfamida, vincristina, prednisona y rituximab en el tratamiento de linfomas no hodgkinianos: estudio de 26 pacientes.

BACKGROUND AND OBJECTIVES: Non-pegylated liposomal doxorubicin is associated with lower cardiac toxicity than conventional doxorubicin, and for that reason it has been used in the treatment of non-Hodgkin's lymphoma (NHL) in old patients or patients with cardiac disease. The objective of this study was to evaluate the efficacy and safety of chemotherapy schedules including non-pegylated liposomal doxorubicin in patients with NHL. PATIENTS AND METHODS: Retrospective study of NHL patients treated with non-pegylated liposomal doxorubicin in two hospitals. In each patient demographic data, clinical and biological variables, as well as therapy, response and toxicity were recorded. RESULTS: Twenty-six patients were included, 14 (58%) of them were women. Median age was 76 years (range 42-86). The most frequent histological diagnosis was diffuse large B cell lymphoma (DLBCL, 20 patients). The stage disease at diagnosis was III/IV in 19 (73%) patients whereas 12 (57%) of the 21 patients with DLBCL and grade 3 follicular lymphoma had a high-risk International Prognostic Index. Three patients had a left ventricular ejection fraction lower than 50% at the time of starting treatment. The most frequent cardiovascular risk factor was hypertension (50% of the patients) and 6 (23%) had previous heart disease. In all cases non-pegylated liposomal doxorubicin was administered as part of the R-COMP schedule (rituximab, cyclophosphamide, vincristin, non-pegylated liposomal doxorubicin and prednisone), in 20 cases (73%) as first-line treatment and in the remaining 6 as salvage therapy. Two patients died after the first cycle of chemotherapy (one because of sudden death and the other due to disease progression). Eleven (61%) out of the 18 patients receiving R-COMP as first-line therapy achieved a complete response (CR), 5 (28%) achieved partial response (PR) and 2 showed progression. Only one out of the 6 patients receiving R-COMP as salvage therapy achieved CR, whereas 3 had PR and 2 did not respond. Grade 3 or 4 neutropenia was observed in 11 (46%) patients and febrile neutropenia in 10 (42%), while only one patient developed grade 4 thrombocytopenia. The median overall survival was 50,7 months (95% confidence interval [95% CI] 8-93.3) and the median disease free survival was 18,4 months (95% CI 18.1-18.7). CONCLUSIONS: In this cohort of patients, most of them old and with cardiovascular risk factors, the administration of non-pegylated liposomal doxorubicin as part of R-COMP regimen was effective and safe.

Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication.

PURPOSE: Fludarabine, cyclophosphamide, and mitoxantrone (FCM) results in a high response rate in previously treated patients with chronic lymphocytic leukemia (CLL). The aim of this study was to investigate FCM as frontline therapy in CLL. EXPERIMENTAL DESIGN: Sixty-nine patients under the age of 65 years with active CLL were treated. Patients received six cycles of fludarabine 25 mg/m(2) i.v. x 3 days, cyclophosphamide 200 mg/m(2) i.v. x 3 days, and mitoxantrone 6 mg/m(2) i.v. x 1 day. Treatment outcome was correlated with clinical and biological variables. The clinical significance of eradicating minimal residual disease (MRD) was also analyzed. RESULTS: The overall response, MRD-negative complete response (CR), MRD-positive CR, nodular partial response (PR), and PR rates were 90%, 26%, 38%, 14%, and 12%, respectively. Severe (grades 3 or 4) neutropenia developed in 10% of the patients. Major and minor infections were reported in 1% and 8% of cases, respectively. Median response duration was 37 months. Patients with del(17p) failed to attain CR. Patients achieving MRD-negative CR had a longer response duration and overall survival than patients with an inferior response. Low serum lactate dehydrogenase levels, low ZAP-70 expression, and mutated IgV(H) genes predicted longer response duration. Finally, both low ZAP-70 and CD38 expression in leukemic cells correlated with MRD-negativity achievement. CONCLUSION: FCM induces a high response rate, including MRD-negative CRs in untreated patients with active CLL. Treatment toxicity is acceptable. Both high ZAP-70 and increased CD38 expression predict failure to obtain MRD-negative response. Patients in whom MRD can be eradicated have longer response duration and overall survival than those with inferior response. These results indicate that FCM can be an ideal companion for chemoimmunotherapy of patients with CLL.

High clinical and molecular response rates with fludarabine, cyclophosphamide and mitoxantrone in previously untreated patients with advanced stage follicular lymphoma.

BACKGROUND: Purine analogs have demonstrated significant activity in patients with follicular lymphoma. The aim of this study was to analyze the efficacy and toxicity of a fludarabine combination as first-line treatment in patients with advanced-stage disease. DESIGN AND METHODS: This is a phase II trial including 120 patients (< or =65 years) treated with 6 cycles of fludarabine, cyclophosphamide and mitoxantrone (FCM). Molecular response was assessed by q-PCR in peripheral blood. RESULTS: Of 119 patients with an assessable response, complete response was achieved in 99 (83%) partial response in 13 (11%) and 7 (6%) did not respond. After treatment, 37 out of 46 (81%) patients achieved molecular response. After a median follow-up of 3.9 years, 32 patients have relapsed. The 5-year progression-free survival was 58% (95% confidence interval: 47-69). Variables associated with a shorter progression-free survival were a poor performance status (ECOG> or =2), > or =2 extranodal sites and high beta2-microglobulin. Sixteen episodes of grade 3-4 infections were observed. Two patients died during therapy (of progressive multifocal leukoencephalopathy and bronchoaspiration respectively). No late toxicity has been observed. Twelve patients died during follow-up (9 after relapse, 2 during chemotherapy, 1 in complete remission after surgery for meningioma). The overall survival at 5 years was 89%. ECOG > or =2 and high beta2-microglobulin were associated with a shorter survival. CONCLUSIONS: FCM results in high complete and molecular response rates, with prolonged response duration in younger patients with advanced-stage follicular lymphoma. The combination of FCM with rituximab as front-line treatment warrants further investigation.

Safety and efficacy of cyclophosphamide, adriamycin, vincristine, prednisone and rituximab in patients with human immunodeficiency virus-associated diffuse large B-cell lymphoma: results of a phase II trial.

Immunochemotherapy with cyclophosphamide, adriamycin, vincristine, prednisone and rituximab (R-CHOP) is the standard treatment in non-immunosuppressed patients with diffuse large B-cell lymphoma (DLBCL), but its adequacy has not been definitively established in patients with human immunodeficiency virus (HIV)-related lymphoma. This phase II trial aimed to evaluate the safety and efficacy of six cycles of R-CHOP in patients with HIV-related DLBCL and to determine whether response to highly active antiretroviral therapy (HAART) had prognostic impact. Patients were eligible if they had performance status <3 and absence of active opportunistic infections. Eighty-one patients were enrolled, 57 in stages III or IV, International Prognostic Index (IPI) 0 or 1 (n = 26), 2 (n = 19), 3 (n = 20) and 4 or 5 (n = 16), and median CD4 lymphocyte count of 0.158 x 10(9)/l. The main adverse events were neutropenia (48% of cycles) and infections (10% of cycles), which were fatal in seven patients. Complete response was achieved in 55 (69%) patients, with an estimated 3-year disease-free survival of 77% and 3-year overall survival of 56%. IPI score and virological response to HAART were the prognostic parameters for response and survival. In HIV-related DLBCL R-CHOP is feasible, safe and effective. The prognosis depends on lymphoma-related parameters and on the response to HAART.

[Population-based incidence of lymphoid neoplasms by histological subtypes in Girona (Spain), 1994-2001]. / Incidencia poblacional de las neoplasias linfoides según el subtipo histológico (Clasificación de la OMS) en Girona, 1994-2001.

BACKGROUND AND OBJECTIVE: We aimed to assess the distribution of the lymphoid neoplasms and their histological subtypes in accordance with the World Health Organization (WHO) classification by calculating their incidences rates in our area. PATIENTS AND METHOD: From January 1994 to December 2001, 1,288 patients diagnosed with lymphoid neoplasms were recruited in the population-based Cancer Registry of Girona. Former pathological and hematological diagnoses were reviewed and some were prospectively reclassified following the latest WHO classification. RESULTS: Following criteria established by WHO classification the distribution of lymphoid neoplasms was as follows: 77.3% B-cell neoplasm, 5.9% T-cell neoplasm, 8.7% Hodgkin lymphoma and 8,2% was unclassifiable. From 1994 TO 2001 the lymphoid neoplasm crude incidence rates was 35.8 per 100,000 men-year, while it was 25.7 new cases per 100,000 women-year. In children (< 15 years old), precursor B-lymphoblastic lymphoma/leukemia (65%) and Hodgkin lymphoma (20%) were the most frequent lymphoid neoplasm, whereas myeloma (17.8%), diffuse large B-cell lymphoma (13.5%) showed the highest incidence rate in adults. CONCLUSIONS: A higher incidence rate of lymphoid neoplasms was found in men in our area compared with other geographical areas in Spain, which could suggested a faster approximation to the pattern observed in industrialized societies. The cause of this geographical distribution is unknown.

High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA.

The aim of the present randomized trial was to compare high-dose therapy (HDT) with continued conventional chemotherapy in patients with multiple myeloma (MM) who responded to the initial treatment. From May 1994 to October 1999, 216 patients (122 men/94 women; stage II or III; Eastern Cooperative Oncology Group [ECOG] score less than 3) entered the study. Initial chemotherapy consisted of 4 cycles of alternating vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, Adriamycin, dexamethasone (VBMCP/VBAD). Responding patients were randomly assigned to receive 8 additional cycles of VBMCP/VBAD, intensification with melphalan 200 mg/m2, or melphalan 140 mg/m2 plus 12 Gy fractionated total body irradiation (TBI). One-hundred sixty-four patients were randomly assigned, 83 to continued chemotherapy and 81 to HDT. The complete remission (CR) rate was significantly higher with HDT (30% vs 11%; P = .002). However, progression-free survival (PFS) was not significantly different between HDT and conventional therapy (median, 42 vs 33 months; P = not significant [NS]), and overall survival (OS) was similar in both groups (median, 61 vs 66 months). Finally, survival after relapse was identical in the 2 arms (15.9 vs 16.4 months). In conclusion, these results show that HDT intensification, when given to myeloma patients who have responded to the initial chemotherapy, significantly increases the CR rate but has no significant impact on PFS or OS.