Reduced Intensity Allogeneic Transplantation for Non-Hodgkin’s Lymphoma: Extended Follow-Up of an Alemtuzumab-Containing Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 401-401 ◽  
Author(s):  
Kirsty J. Thomson ◽  
Emma C. Morris ◽  
Don Milligan ◽  
Gordon Cook ◽  
Jim Cavet ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Autologous Transplantation ◽  
Allogeneic Transplantation ◽  
Low Grade ◽  
High Grade ◽  
Reduced Intensity Conditioning ◽  
Mantle Cell ◽  
Reduced Intensity

Abstract Allogeneic transplantation with reduced intensity conditioning is increasingly being used in patients with non-Hodgkin’s Lymphoma (NHL) who fail standard therapy. We report extended follow-up on 121 patients with NHL, who underwent allogeneic transplantation with reduced intensity conditioning at 8 UK centres. Conditioning was with fludarabine 150mg/m2, melphalan 140mg/m2 and alemtuzumab (60–120mg). Cyclosporin A was administered at 3mg/kg from day-1, and stem cell source was bone marrow or PBSC. Diagnoses were in 3 categories: low grade follicular NHL (n=50), mantle cell lymphoma (n=21), and high-grade NHL (n=50, including transformed low grade disease n=15). Donors were HLA-matched siblings in 75 (62%), and unrelated in 46 (38%), of whom 18 were HLA-mismatched at up to 3/10 loci. 48% of patients had failed previous autologous transplantation. Median follow-up was 35 months (1–78). For the group with low grade follicular NHL (n=50), estimated overall survival (OS) was 76% at 1yr and 67% at 4yrs, and non-relapse mortality (NRM) was 16% at 4yrs. Disease relapse or progression occurred in 12 patients, of whom 8 received donor lymphocyte infusions (DLI), with responses in 6. Current progression-free survival (cPFS) is 68% at 4yrs. For the group with mantle cell lymphoma (n=21), estimated OS was 83% at 4yrs, NRM was 11% at 4yrs and relapse or progression occurred in 6 patients. Three patients received DLI, with non-sustained responses in 2. Current PFS is 43% at 4yrs. For high-grade NHL (n=50), estimated OS was 52% at 1yr and 45% at 4yrs. Prior autologous transplantation was common in this group (72%), and NRM was higher at 34% at 1yr and 40% at 4yrs. Progression/relapse occurred in 15 patients, of whom 10 received donor lymphocytes, with responses in 5. Current PFS is 48% at 1yr and 43% at 4yrs. These results, from patients who were often heavily pre-treated, including having failed autologous transplantation, provide encouraging evidence to support the application of reduced intensity allogeneic transplants in NHL. NRM in low grade follicular or mantle cell lymphoma is low, consistent with the use of T cell depletion, and graft-versus-lymphoma effects can be induced with DLI in a subset of cases. The data in follicular lymphoma, in particular, supports consideration of this therapy earlier in the disease. In high-grade disease, NRM appears to be higher, but durable remissions are attainable in a proportion of patients.

Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 619-626 ◽  
Author(s):  
Roberto Chiarle ◽  
Leo M. Budel ◽  
Jeffrey Skolnik ◽  
Glauco Frizzera ◽  
Marco Chilosi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Protein Degradation ◽  
Mantle Cell Lymphoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Low Grade ◽  
High Grade ◽  
Ki 67 ◽  
Mantle Cell

Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the deregulated expression of cyclin D1 by t(11;14). The molecular mechanisms responsible for MCL's clinical behavior remain unclear. The authors have investigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 in 110 MCLs, relating their expression to proliferative activity (Ki-67). For comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas. p53 was detected more frequently in large-cell MCL (l-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DLCL (8 of 19). In MCL and DLCL, the percentage of E2F-1+ nuclei was high, correlating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 of 19) showed a loss of p27; MALT and CLL/SLL, however, were p27 positive. Reverse transcription–polymerase chain reaction and in vitro protein degradation assays demonstrated that MCLs have normal p27 mRNA expression but increased p27 protein degradation activity via the proteasome pathway. Correlation of MCL p53 and p27 expression with clinical data showed an association between reduced overall survival rates and the overexpression of p53 (P = .001), the loss of p27 (P = .002), or both. Loss of p27 identified patients with a worse clinical outcome among p53 negative cases (P = .002). These findings demonstrated that MCL has a distinct cell cycle protein expression similar to that of high-grade lymphoma. The loss of p27 and the overexpression of p53 in MCL are prognostic markers that identify patients at high risk. The demonstration that low levels of p27 in MCL result from enhanced proteasome-mediated degradation should encourage additional clinical trials. (Blood. 2000;95:619-626)

High Response Rate to DLI Based Strategies for the Treatment of Refractory Disease/Relapse Following Allogeneic HSCT for Lymphoproliferative Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1653-1653
Author(s):  
Nigel H. Russell ◽  
Jenny L. Byrne ◽  
Emma P. Das-Gupta ◽  
Michelle Gilyead ◽  
Andy P. Haynes
Keyword(s):  
Mantle Cell Lymphoma ◽  
Acute Gvhd ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Lymphoproliferative Disease ◽  
High Response Rate ◽  
Low Grade ◽  
High Grade ◽  
Allogeneic Hsct ◽  
Mantle Cell

Abstract Allogeneic HSCT is increasingly being performed for lymphoproliferative disease, particularly with reduced intensity conditioning (RIC). DLI are an important part of this strategy however there is a paucity of information in this setting although responses have been reported in Hodgkin’s disease and follicular lymphoma. We have treated 17 patients (median age 51 year; 30–62yr) with refractory disease (n=7) or disease relapse (n=10) following allogeneic HSCT for lymphoma with a DLI based strategy. The diagnosis was CLL, including 1 Richter’s (n=5); mantle cell lymphoma (n=4); high grade NHL (n=4) and follicular NHL (n=4). 15 patients received RIC transplants with either Beam/Alemtuzumab (n=11), or fludarabine/melphelan/alemtuzumab (n=4). Two patients received myeloablative conditioning with TBI and cyclophosphamide. The median time to DLI was 0.96 years (0.23 to 4.58yr) and in 15/17 the donor was a matched sibling (n=13) or 1 antigen mismatched sibling (n=2) and in 2 cases was an unrelated donor. At DLI, 6 patients had mixed chimaerism (20–95%) and 8 had full donor chimaerism with the chimaerism status being unknown in 5 cases. Patients with low grade disease received DLI either alone (n=7) or following initial radiotherapy (n=1). Patients with high-grade NHL, MCL or Richter’s transformation of CLL (n=11) all received chemtherapy pre-DLI. For the 15 sibling donors the median first dose of CD3+ cells infused was 2.0 x 10 7/kg ( range 0.5–6 x 10 7/kg) following which 6 achieved CR. 6 patients received a 2nd infusion (median dose 5 x 10 7/kg) with 2 achieving CR and 1 patient receiving a 3rd DLI and achieving CR. Both MUD DLI recipients achieved a CR after 2 and 3 infusions. Overall 10 out of 17 patients achieved a CR including 3/4 patients with CLL, 4/4 with MCL; 3/4 with follicular NHL but none of the 5 patients with high-grade NHL/Richter’s transformation responded. The median CD3 cell dose required to achieve CR for sibling donors was 2x 107/kg whereas non-responders received a median of 5.0 x 107/kg. An additional patient with CLL who developed aplasia following the first DLI had a second transplant from the same donor and is in CR at 14m giving a final overall CR rate of 70%. Response to DLI was independent of chimaerism status at relapse. Acute GvHD developed in 11 patients and was grade II in 8/10 and grade 111/IV in 3 cases. 1 patient died in CR of acute GvHD. Chronic GvHD developed in 9 of 11 surviving patients. Only 1 patient with mantle cell lymphoma has relapsed at 18m post-DLI. The median follow-up for the surviving patients is 34m (range 6m–60m). The overall survival at a median of 30 months post DLI is 58%. We conclude that lymphoma patients, particularly those with low grade NHL including mantle cell lymphoma relapsing following an allogeneic transplant have a high response rate to DLI based strategies,superior to that seen in myeloma and comparable to that seen in CML. Furthermore these responses appear durable with a low risk of relapse. Patients with high-grade disease appear to have a poor response rate despite using pre-DLI chemotherapy

scholarly journals Myeloablative or Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Mantle Cell Lymphoma? a Systematic Review and Meta-Analysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2097-2097
Author(s):  
Mohamed A. Kharfan-Dabaja ◽  
Tea Reljic ◽  
Jessica El-Asmar ◽  
Taiga Nishihori ◽  
Ernesto Ayala ◽  
...  
Keyword(s):  
Systematic Review ◽  
Mantle Cell Lymphoma ◽  
Hematopoietic Cell Transplantation ◽  
Cell Lymphoma ◽  
Meta Analysis ◽  
Chronic Gvhd ◽  
Pooled Analysis ◽  
Reduced Intensity Conditioning ◽  
Mantle Cell ◽  
Reduced Intensity

Abstract Background: Despite availability of novel agents to treat mantle cell lymphoma (MCL), the disease remains incurable with standard therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) is generally offered in the setting of relapsed or refractory disease. Reduced intensity conditioning (RIC) allo-HCT has expanded availability of the procedure for patients deemed ineligible to receive a myeloablative (MAC) regimen in the past due to advanced age or associated comorbidities. We performed a systematic review and meta-analysis to assess the totality of evidence pertaining to efficacy of allo-HCT (RIC or MAC) in MCL. Materials and methods: A comprehensive search of MEDLINE/PUBMED from inception until July 04, 2015 was undertaken. Data were collected on treatment benefits (event-free (EFS), progression-free (PFS) and overall survival (OS) and harms (non-relapse mortality (NRM) and graft-versus host disease (GVHD)). Results: Fifty-nine manuscripts were identified of which 16 met inclusion criteria (710 patients). For RIC regimens, pooled analysis of 9 studies (n=507) showed an EFS/PFS rate of 47% (95%CI=32-61%) and an OS rate of 53% (95%CI=39-67%). NRM rate for RIC regimens from a pooled analysis of 9 studies (n=507) was 24% (95%CI=16-33%). Incidences of acute (grade 2-4) and chronic GVHD (all grades) following a RIC regimen were 31% (95%CI=20-45%, pooled from 6 studies (n=299)) and 42% (95%CI=30-54%, pooled from 7 studies (n=369)), respectively. For MAC regimens, pooled analysis of 4 studies (n=124) showed an EFS/PFS rate of 34% (95%CI=21-50%). The OS rate was 40% (95%CI=28-52%) from a pooled analysis of 5 studies (n=138). NRM rate for MAC regimens was 37% (95%CI=23-51%) based on a pooled analysis of 4 studies (n=119); only 1 study reported incidence of acute (grade 2-4) and chronic GVHD (all grades) of 36% (95%CI=23-50%) and 35% (95%CI=22-48%), respectively. When analysis was restricted to the late/salvage setting, we analyzed aforementioned outcomes regardless of regimen intensity (RIC+MAC) as well as specifically to RIC or MAC. When RIC and MAC regimens were combined, the pooled analysis of 12 studies (n=578) showed an EFS/PFS rate of 34% (95%=23-46%) and OS rate of 43% (95%CI=32-53%). The NRM rate was 30% (95%CI=20-41%, pooled analysis of 11 studies (n=563)). For RIC regimens in the late/salvage setting, the pooled analysis of 7 studies (n=436) showed an EFS/PFS rate of 40% (95%CI=26-56%) and OS rate of 48% (95%CI=33-62%). For MAC regimens in the late/salvage setting, the pooled analysis of 3 studies (n=105) showed an EFS/PFS rate of 35% (95%CI=17-55%) and OS rate of 38% (95%CI=22-56%). The observed heterogeneity was statistically significant among RIC studies for outcome of OS (p < 0.0001) but not for MAC (p= 0.1315). Conclusion: These results demonstrate that allo-HCT is an effective strategy for treatment of MCL even in the late/salvage setting. On the basis of a relatively lower NRM and a slightly better EFS/PFS and OS, RIC regimens may be the preferred choice when an allo-HCT is being considered for MCL. However, a prospective comparative study in this setting is necessary to generate more conclusive evidence. Disclosures No relevant conflicts of interest to declare.

scholarly journals Autologous or Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Chemotherapy-Sensitive Mantle-Cell Lymphoma: Analysis of Transplantation Timing and Modality

2014 ◽  
Vol 32 (4) ◽  
pp. 273-281 ◽  
Author(s):  
Timothy S. Fenske ◽  
Mei-Jie Zhang ◽  
Jeanette Carreras ◽  
Ernesto Ayala ◽  
Linda J. Burns ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Mantle Cell Lymphoma ◽  
Cell Transplantation ◽  
Cell Lymphoma ◽  
Disease Course ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Mantle Cell ◽  
Reduced Intensity

Purpose To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course. Patients and Methods In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients. Results Auto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT. Conclusion For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.

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