Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma.

BACKGROUND: To evaluate the clinical outcome of patients with relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and high-dose therapy with autotransplant. PATIENTS AND METHODS: Sixty-four patients were enrolled in the trial. Primary end point was progression-free survival (PFS). Secondary end points were the in vivo purging effect on stem-cell harvest and the impact of molecular response on the outcome. RESULTS: At enrollment, 59% of patients were PCR+ for bcl-2 rearrangement in bone marrow (PCR-informative). After the immunochemotherapy, before mobilization, 97% obtained complete response or partial response and 87% of patients informative for bcl-2 were molecularly negative. Sixty-one patients proceeded to in vivo purging and peripheral blood stem cell (PBSC) mobilization with rituximab and high-dose AraC. The median number of CD34+ cells collected was 16.6 x 10(6)/kg. Of 33 PCR-informative patients, the harvests resulted in PCR- in all. Fifty-eight patients received high-dose therapy and autotransplant of in vivo purged PBSC. After a median follow-up of 3.5 years, 41 patients are in complete remission. Five-year PFS is 59%. CONCLUSION: This study demonstrates that patients with advanced relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and autotransplant may obtain long-lasting PFS. In bcl-2-positive patients, in vivo purging allows the harvest of lymphoma-free PBSC. Absence of the bcl-2 rearrangement after autotransplant is associated with persistent clinical remission.

Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi).

A prospective multicenter program was performed to evaluate the combination of rituximab and high-dose (hd) sequential chemotherapy delivered with multiple autologous peripheral blood progenitor cell (PBPC) support (R-HDS-maps regimen) in previously untreated patients with diffuse large B-cell lymphoma (DLB-CL) and age-adjusted International Prognostic Score (aaIPI) score 2-3. R-HDS-maps includes: (i) three APO courses; (ii) sequential administration of hd-cyclophosphamide (CY), hd-Ara-C, both supplemented with rituximab, hd-etoposide/cisplatin, PBPC harvests, following hd-CY and hd-Ara-C; (iii) hd-mitoxantrone (hd-Mito)/L-Pam + 2 further rituximab doses; (iv) involved-field radiotherapy. PBPC rescue was scheduled following Ara-C, etoposide/cisplatin and Mito/L-Pam. Between 1999 and 2004, 112 consecutive patients aged <65 years (74 score 2, 38 score 3) entered the study protocol. There were five early and two late toxic deaths. Overall 90 patients (80%) reached clinical remission (CR); at a median 48 months follow-up, 87 (78%) patients are alive, 82 (73%) in continuous CR, with 4 year overall survival (OS) and event-free survival (EFS) projections of 76% (CI 68-85%) and 73% (CI 64-81%), respectively. There were no significant differences in OS and EFS between subgroups with Germinal-Center and Activated B-cell phenotype. Thus, life expectancy of younger patients with aaIPI 2-3 DLB-CL is improved with the early administration of rituximab-supplemented intensive chemotherapy compared with the poor outcome following conventional chemotherapy.

Vinorelbine and prednisone in frail elderly patients with intermediate-high grade non-Hodgkin's lymphomas.

BACKGROUND: Frail patients with non-Hodgkin's lymphoma (NHL) are generally excluded from clinical trials and not even treated. The aim of this study was to evaluate the efficacy and tolerability of vinorelbine and prednisone in frail elderly patients with NHL. PATIENTS AND METHODS: Thirty consecutive frail elderly patients were entered in a phase II study with vinorelbine 25 mg/m2 i.v. on days 1 and 8 and oral prednisone 30 mg total dose on days 1-8 for six cycles. Criteria of frailty were age > or =80 years, or age > or =70 years and three or more comorbidities of grade 3 or at least one comorbidity of grade 4 according to the Cumulative Illness Rating Scale (CIRS), or not self-sufficient or the presence of one or more geriatric syndromes. RESULTS: Of 30 evaluable patients, three (10.0%) achieved a complete response (CR), nine (30.0%) showed a partial response (PR), while 10 presented with stable disease and eight with progressive disease. The median duration of CR was 29 months (range 5-36 months), and the median duration of PR was 1 month (range 1-22 months). Three patients had grade 3 neutropenia and one had grade 4. One grade 4 neurotoxicity was observed. Three patients died because of heart failure within 28 days of therapy, and one patient died after 4 days because of rapid progression. The median overall survival was only 10 months. CONCLUSION: Vinorelbine and prednisone is a relatively non-toxic combination with modest activity in frail patients with NHL. If initial aggressive chemotherapy has been excluded, this combination could be tried to obtain a temporary palliation.

Recombinant interleukin-2 treatment before and after autologous stem cell transplantation in hematologic malignancies: clinical and immunologic effects.

Autologous bone marrow transplantation (ABMT) for hematologic malignancies is associated with a high relapse rate. Interleukin-2 (IL-2) administration is a therapy that may prevent relapse if used when the tumor burden is minimal. In this study we administered recombinant IL-2 (rIL-2) therapy to 12 patients affected by hematologic malignancies either before or after autologous stem cell transplantation (ASCT). rIL-2 was given by a 6 day continuous intravenous infusion with escalating doses, up to 18 x 10(6)/m2/day, depending on patient tolerance. The functional immune responses of the patients were assessed as natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic activities and in vitro interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synthesis. During rIL-2 treatment, the expected side effects occurred; only 3 patients, who showed severe cardiovascular toxicity, required suspension of the treatment. All toxicities reversed after the end of the therapy. Immunologic monitoring was carried out the day before starting rIL-2 infusion and then repeated on days 3, 7, and 14 after rIL-2 was discontinued. Following every rIL-2 course, a pronounced increase in CD3+, CD8+, CD56+ cells was found, with a peak value on day 3. The NK and LAK activities showed a significant increase on day 3 (p < 0.001) over pretherapy values; the increase lasted until day 14, although the difference at later time points was not significant. Before transplant the synthesis of both IFN-gamma and TNF-alpha decreased following rIL-2 therapy, whereas higher levels of these lymphokines were found after posttransplant rIL-2 courses.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood stem cells autografts in patients with high risk multiple myeloma.

Five patients with high risk multiple myeloma not responsive to standard chemotherapy were treated by high-dose chemotherapy (Melphalan, Cyclophosphamide) (HDC) and total body irradiation (TBI) followed by autografting with blood stem cells. These cells were previously collected by leukaphereses from eight to twelve occasions during hematopoietic recovery following profound aplasia induced by each course of intensive chemotherapy (Vincristine, Adriamycin, Cyclosphosphamide, Prednisone) when the patient reached a neutrophil count of 1,000/microliters and a platelet count of 100,000/microliters. No patients had evidence of tumor plasmacells in leukaphereses products using cytology, immunocytochemistry and immunofluorescence. At this time the patient 5 is not evaluable because of the short follow-up. One died at day 30 from heart failure. All living patients achieved a complete remission which persisted at a follow-up of 300, 261 and 136 days. Autologous blood derived hematopoietic stem cells induced successful and sustained engraftment in all living patients. Our results indicate the feasibility of this therapeutic approach over allogenic or autologous bone marrow transplantation in selected patients with high tumour mass multiple myeloma.

Phenotype of chronic lymphocytic leukemia (CLL) B-cells. B-CLL cells express the Leu-8 antigen.

In the present report we studied the phenotype of peripheral blood mononuclear cells (PBMC) from 25 patients with B-cell chronic lymphocytic leukemia (CLL). Cells from all the cases expressed monoclonal surface immunoglobulins (SmIg), formed rosettes with mouse erythrocytes (MRFC) and were positive with OKB 2 and OKIa monoclonal antibodies. In addition, CCB 1 monoclonal antibody was positive in 17 out of 20, Leu-1 in 18 out of 21 and Leu-8 in 23 out of 25 cases. Double labelling experiments confirmed that the Leu-8 antigen was co-expressed on Leu-1+, CCB2+, HLA-DR+ B-CLL cells. Thus, B-CLL cells generally express the SmIg+, MRFC+, Leu-1+, OKB2+, Leu-8+ phenotype. Since it is known that normal peripheral blood B cells may be divided into two subpopulations according to Leu-8 expression, our data indicate that B-CLL cells originate from the more immature Leu-8+ B-cell subset which will respond to anti-IgM, whereas it reacts poorly to pokeweed mitogen.

Unusual phenotype (Leu 7+, OKT4+, OKM1+) expressed by cells from a patient with an abnormal expansion of granular lymphocytes.

We report the case of a 70-year-old female with a lymphocytosis which was casually detected during a routine examination. Immunological studies revealed the expansion of granular lymphocytes (GL) with the following, previously undescribed phenotype: Leu 7+, OKT3+, OKT4+, OKT8-, OKM1+. These cells were tested for their functional activities and found to exert neither helper nor suppressor functions in in vitro tests. Cytotoxic activities demonstrated a strong ADCC and a markedly reduced NK function. 1 year later the clinical course has remained good without any treatment and we suggest that this case should be classified as an abnormal expansion of GL, despite the OKT4 positivity of the cells. Our data point out the importance of a careful immunological study of cells from these rare patients and suggest the existence of a normal GL population expressing the OKT4 phenotype, which is possibly expanded in this patient.