(1/1024) High-dose therapy with autologous or allogeneic transplantation as salvage therapy for small cleaved cell lymphoma of follicular center cell origin.
Between 1985 and 1996, 51 patients with relapsed or refractory small cleaved cell lymphoma (SCCL) received high-dose chemotherapy +/- TBI in conjunction with autologous (ABMT) (36 patients) or allogeneic transplantation (15 patients). Patients were eligible for ABMT if the bone marrow biopsy done prior to the planned transplant did not reveal microscopic involvement with SCCL. Patients receiving ABMT had a median age of 48 years, had received a median of 2.5 chemotherapy regimens prior to transplantation, and were transplanted a median of 35.5 months from diagnosis. Among patients receiving ABMT, 5 year actuarial survival was 56+/-11%. Median survival was 126+ months, and median survival from diagnosis was 191 months. Univariate and multivariate analysis identified sensitive disease as the best predictor of a favorable response. Five-year actuarial survival was 66+/-12% for patients with sensitive disease at the time of transplant as compared to 29+/-17% for patients with resistant disease, P = 0.015. Median survival in patients with sensitive disease at the time of ABMT was 126+ months. By univariate analysis, survival was significantly better for patients receiving ABMT as compared to patients receiving allogeneic transplants. Median survival following allogeneic transplantation was 5 months; 5 year actuarial survival was 15+/-13%. In a multivariate analysis, which considered autologous vs allogeneic transplantation, sensitive vs resistant disease, <3 vs > or = 3 prior treatments, and prior bone marrow involvement, allogeneic transplantation was significantly associated with poor survival. Treatment-related mortality occurred in eight of 15 patients receiving allogeneic transplantation and limited the effectiveness of this therapy. High-dose therapy in conjunction with ABMT is effective therapy for patients with SCCL whose disease is sensitive to chemotherapy and whose marrows are microscopically free of disease. Because of possible selection bias, it has not been proven that this approach increases survival in these patients. Treatment-related mortality limits the effectiveness of allogeneic transplantation in SCCL. (+info)
(2/1024) Nonimmunoglobulin gene hypermutation in germinal center B cells.
Somatic hypermutation is the most critical mechanism underlying the diversification of Ig genes. Although mutation occurs specifically in B cells during the germinal center reaction, it remains a matter of debate whether the mutation machinery also targets non-Ig genes. We have studied mutations in the 5' noncoding region of the Bcl6 gene in different subtypes of lymphomas. We found frequent hypermutation in follicular lymphoma (25 of 59 = 42%) (germinal center cell origin) and mucosa-associated lymphoid tissue (MALT) lymphoma (19 of 45 = 42%) (postgerminal center), but only occasionally in mantle cell lymphoma (1 of 21 = 4.8%) (pregerminal center). Most mutations were outside the motifs potentially important for transcription, suggesting they were not important in lymphomagenesis but may, like Ig mutation, represent an inherent feature of the lymphoma precursor cells. Therefore, we investigated their normal cell counterparts microdissected from a reactive tonsil. Bcl6 mutation was found in 13 of 24 (54%) clones from the germinal centre but only in 1 of 24 (4%) clones from the naive B cells of the mantle zone. The frequency, distribution, and nature of these mutations were similar to those resulting from the Ig hypermutation process. The results show unequivocal evidence of non-Ig gene hypermutation in germinal center B cells and provide fresh insights into the process of hypermutation and lymphomagenesis. (+info)
(3/1024) Follicular large cell lymphoma: an aggressive lymphoma that often presents with favorable prognostic features.
It is debated whether follicular large cell lymphoma (FLCL) has a clinical behavior that is distinct from indolent follicular lymphomas, and whether there is a subset of patients who can be potentially cured. We report here our experience with 100 FLCL patients treated at our institution since 1984 with three successive programs. We evaluated the predictive value of pretreatment clinical features, including two risk models, the Tumor Score System and the International Prognostic Index (IPI). With a median follow-up of 67 months, the 5-year survival is 72% and the failure-free survival (FFS) is 67%, with a possible plateau in the FFS curve, particularly for patients with stage I-III disease. Features associated with shorter survival included age >/=60, elevated lactic dehydrogenase (LDH) or beta-2-microglobulin (beta2M), advanced stage, and bone marrow involvement. Stage III patients had significantly better survival than stage IV patients (P <.05). By the IPI and Tumor Score System, 80% of the patients were in the lower risk groups; both systems stratified patients into prognostic groups. Patients with FLCL have clinical features and response to treatment similar to that reported for diffuse large cell lymphoma. Prognostic risk systems for aggressive lymphomas are useful for FLCL. A meaningful fraction of patients may possibly be cured when treated as aggressive lymphomas. (+info)
(4/1024) Autologous stem cell transplantation in advanced follicular lymphoma. A single center experience.
BACKGROUND AND OBJECTIVE: The use of intensive therapy supported by autologous stem cell transplantation (ASCT) is being investigated as treatment for poor-prognosis follicular lymphomas (FL). A single-center experience is herein reported. DESIGN AND METHODS: From September 1990 to October 1997, 30 consecutive patients (pts) with advanced FL received transplants, 8 of bone marrow and 22 of peripheral blood. Thirteen harvests were purged by an immunomagnetic method using anti-B antibodies. Twenty-seven patients received salvage chemotherapy (CT) before ASCT with the objective of reaching this procedure in the best possible response. The disease status at ASCT was: 1(st) CR in 7 pts, > or =2(nd) CR in 6 pts, PR in 10 pts, untreated relapse in 2 pts and chemoresistant disease in 5 pts. RESULTS: There was only one transplant-related death (one month after ASTC). With a median follow-up of 19 (1-89) months, 27 pts are alive, 8 pts have relapsed/progressed at a median time of 11 (6-22) months after ASCT. The estimated 2-year PFS and OS are 57% (95% CI, 34-81%) and 83% (95% CI, 64-100%). When comparing the progression-free interval (PFI) before salvage CT and ASCT and the PFI after ASCT, of 17 evaluable pts, 10 had a PFI after ASCT longer than the previous interval, and 5 additional pts remain in CR/PR with a follow-up that has not yet reached the duration of pre-transplant response. By contrast, 2 pts had a short post-transplant response. INTERPRETATION AND CONCLUSIONS: High-dose therapy followed by ASCT obtains a high rate of responses, frequently longer than any previous PFI. Additional follow-up is necessary to determine whether there is any "plateau" in response duration and to define what proportion of pts may be cured with ASCT in this setting. (+info)
(5/1024) Correlation of bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma.
The t(14;18) translocation, which involves the bcl-2 oncogene, occurs in follicular lymphomas (FL) at two common sites: the major breakpoint region (MBR) and the minor cluster region (mcr). The biological and clinical significance of these breakpoints is unknown. The bcl-2 breakpoint site was determined in 247 previously untreated patients (49% men; median age 52 years) with indolent FL (155 grade I, 83 grade II, and 8 grade III) to correlate it with pretreatment characteristics, response, and outcome. The bcl-2 breakpoint site was determined by a polymerase chain reaction method of peripheral blood (all cases), bone marrows (149 cases), and fresh lymph node biopsy specimens (68 cases). The breakpoint site occurred at MBR in 175 cases (71%) and at mcr in 27 (11%). In 45 cases (18%), no breakpoint was detected (germline). No significant relationship was found between the rearrangements and the expression of BLC-2 and BAX proteins. Patients' germline for MBR and mcr tended to present more frequently with stage IV disease and higher beta2-microglobulin (beta2M) levels, whereas mcr-rearranged patients presented more frequently with early stage and normal beta2M. The complete response rate of germline patients was significantly lower than that of MBR and mcr patients. An estimated 3-year failure-free survival (FFS) for mcr, MBR, and germline cases was 95%, 76%, and 57%, respectively (P <.001). The bcl-2 breakpoint site was independent of serum beta2M and lactate dehydrogenase in its correlation with FFS. In conclusion, the bcl-2 rearrangement site is an important prognostic factor in indolent FL, useful to identify patients who may require different treatment. (+info)
(6/1024) Immunomagnetic bone marrow (BM) and peripheral blood progenitor cell (PBPC) purging in follicular lymphoma (FL).
Twenty-nine B cell follicular lymphoma (FL) patients had their BM (n = 12) or PBPC (n = 17) purged using a panel of monoclonal antibodies and immunomagnetic beads (IMB). The median recovery of nucleated cells (NC) and CD34+ cells was 59.3% (40.5-74) and 56.1% (30.8-82.9) in BM and 77.2% (64.7-88.3) and 73.5% (61.5-98.6) in PBPC (P<0.0005). A median of >1.62 and >1.02 log of target cell depletion was achieved as judged by flow cytometry analysis in BM and PBPC, respectively. Of 29% of initial harvests that had a bcl2 PCR-amplified signal, 37.5% became PCR negative in the final purged products. Absorbed cells containing IMB-target cell complexes gave bcl2 rearrangement signal in 20% of samples in which the start and final purged components were negative. Twenty-three of 26 patients receiving an autologous purged product are evaluable for engraftment. Median time to reach an ANC >0.5x10(9)/l and platelet count >20x10(9)/l was 21 (11-43) and 41 days (13-70) for BM (n = 9) and 14 (10-31) and 14 (8-37) for PBPC (n = 14) autografted patients (P = 0.01 and 0.001). One patient did not engraft and was rescued with a back-up BM. These data demonstrate that this indirect immunomagnetic technique is able to achieve a high grade of lymphoma cell depletion in BM and PBPC and that these purged products are capable of rapid engraftment after autologous transplantation. (+info)
(7/1024) Development and validation of a quantitative polymerase chain reaction assay to evaluate minimal residual disease for T-cell acute lymphoblastic leukemia and follicular lymphoma.
The presence of occult disease in cancer patients after therapy is one of the major problems faced by oncologists. For example, although 95% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients have a complete therapeutic response to multiagent chemotherapy, half will relapse, indicating that they must have harbored low levels of residual cancer cells at the end of therapy. Sensitive detection assays promise to help identify those patients that carry this minimal residual disease (MRD) and are at risk of relapse. We have developed and validated a quantitative polymerase chain reaction (PCR) assay targeting tumor-specific chromosomal rearrangements, including del(1) involving the tal-1 locus in pediatric T-ALL and t(14;18) involving the bcl-2 locus in follicular lymphoma. This quantitative PCR assay utilizes a synthetic internal calibration standard (ICS) that contains priming sequences identical to those found flanking the chromosomal rearrangement breakpoints. Using this ICS-PCR method, the limits of detection were 5 tumor cells at ratios of 1 tumor cell in 10(5) normal cells and a linear range up to 100% tumor cells. This ICS-PCR method has also performed well in terms of precision and accuracy as indicated by low coefficients of variation, minimal random, proportional, and constant errors, and good clinical sensitivity and specificity characteristics. This technique will allow for the evaluation of parameters such as the rate of therapeutic response and the levels of MRD as predictors of patient outcome. (+info)
(8/1024) Management of non-Hodgkin's lymphomas.
The non-Hodgkin's lymphomas (NHL) are a heterogeneous group of disorders characterised by malignant proliferation of lymphoid cells. The cellular origin is relatively well established with subtypes corresponding to the various stages of lymphocyte differentiation. The term encompasses a hotchpotch of conditions with very different morphological appearance, behaviour and clinical outcome. NHL comprise 2.4% of all cancers, with incidence increasing with age. The commonest presentation is with progressive lymphadenopathy, though extranodal manifestations are present in a significant proportion. The clinical behaviour ranges from a benign, indolent course to rapidly progressive disease; prognosis varies from weeks to many years. Treatment is correspondingly diverse, from 'watchful waiting' to high-dose chemotherapy with bone marrow stem cell transplantation. Cure is possible in an increasing number of patients and much interest currently lies in identifying patients with high-risk disease necessitating the use of intensive treatment regimens. (+info)