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)

Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2385-2387 ◽  
Author(s):  
Olaf Determann ◽  
Eva Hoster ◽  
German Ott ◽  
Heinz Wolfram Bernd ◽  
Christoph Loddenkemper ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Randomized Trials ◽  
Cell Lymphoma ◽  
Treated Patient ◽  
Low Grade ◽  
Advanced Stage ◽  
Ki 67 ◽  
Mantle Cell ◽  
Anti Cd20

Clinical outcome of mantle cell lymphoma (MCL) is highly heterogeneous. Tumor cell proliferation as assessed by the Ki-67 index has been shown to yield prognostic information on MCL in many studies using heterogeneously treated patient cohorts. The prognostic value of the Ki-67 index in patients treated with anti-CD20 therapy has not been studied so far. We analyzed the Ki-67 index at primary diagnosis in 249 advanced-stage MCL patients treated within randomized trials. Ki-67 showed high prognostic relevance for overall survival (relative risk 1.27 for 10% higher Ki-67, P < .001), also independently from clinical prognostic factors. The 3 groups with different Ki-67 index of less than 10%, 10% to less than 30%, and 30% or more showed significantly different overall survival in patients treated with CHOP (P = .001) as well as in patients treated with CHOP in combination with anti-CD20 therapy (R-CHOP, P = .013). Thus, the Ki-67 index remains an important prognostic marker in the era of anti-CD20 therapy. The Euro-pean MCL study is registered at www.ClinicalTrials.gov as #NCT00016887.

Rituximab maintenance improves progression-free and overall survival rates after combined immuno-chemotherapy (R-FCM) in patients with relapsed follicular and mantle cell lymphoma: Final results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7502-7502 ◽  
Author(s):  
M. Dreyling ◽  
R. Forstpointner ◽  
M. Gramatzki ◽  
H. Böck ◽  
M. Hänel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Remission Induction ◽  
Low Grade ◽  
Free Survival ◽  
Mantle Cell ◽  
The Impact

7502 Background: Rituximab (R) prolongs the progression-free survival (PFS) in patients with follicular lymphoma (FL) when given either simultaneously with or as maintenance after chemotherapy only. Methods: In the current study the impact of R maintenance after remission induction with an R-containing combined immuno-chemotherapy (R-FCM) was evaluated. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized 4 courses of chemotherapy with Fludarabine (25 mg/m2/d days 1–3), Cyclophosphamide (200 mg/m2/d days 1–3) and Mitoxantrone (8 mg/m2/d day 1) (FCM) ± Rituximab (375 mg/m2/d day 0). Patients entering a complete (CR) or partial remission (PR) underwent a second randomization for R maintenance (4 weekly doses (375 mg/m2/d) at three and nine months after end of induction) or observation only. Randomization was stratified for histology, prior therapies (up to 2 lines vs. >2), induction (±R), and response (CR vs. PR). After improved outcome of the R-FCM arm had been observed in the initial 147 randomized patients, all subsequent patients received a combined immuno-chemotherapy induction. Results: 176 of 195 randomized cases are evaluable, 138 of whom had received an R-containing induction. In these patients (as well as the total group) the median PFS after end of induction has not been reached in the R-maintenance arm in contrast to 17 months in patients with no further treatment (p = 0.001). This improvement was seen both in FL (n = 81; p = 0,035) and MCL (n = 47; p = 0,049). More importantly, overall survival rate was also improved after R maintenance with borderline significance (3 y rate 82% vs. 55%; p = 0,056). No major sided effects of R maintenance have been observed and the rate of serious infections was similar in both study arms (p = 0.72). Conclusions: The final analysis of this study confirms that R maintenance after combined immuno-chemotherapy (R-FCM) is highly effective and improves the progression-free survival—with a strong trend towards improved overall survival—of patients with relapsed FL and MCL. [Table: see text]

MicroRNA Signature Obtained From the Comparison of Aggressive With Indolent Non-Hodgkin Lymphomas: Potential Prognostic Value in Mantle-Cell Lymphoma

2013 ◽  
Vol 31 (23) ◽  
pp. 2903-2911 ◽  
Author(s):  
Rashmi S. Goswami ◽  
Eshetu G. Atenafu ◽  
Yali Xuan ◽  
Levi Waldron ◽  
Patricia P. Reis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Prognostic Model ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Differentially Expressed ◽  
Training Set ◽  
Ki 67 ◽  
Mantle Cell

Purpose Mantle-cell lymphoma (MCL) has a variable natural history but is incurable with current therapies. MicroRNAs (miRs) are useful in prognostic assessment of cancer. We determined an miR signature defining aggressiveness in B-cell non-Hodgkin lymphomas (NHL) and assessed whether this signature aids in MCL prognosis. Methods We assessed miR expression in a training set of 43 NHL cases. The miR signature was validated in 44 additional cases and examined on a training set of 119 MCL cases from four institutions in Canada. miRs significantly associated with overall survival were examined in an independent cohort of 114 MCL cases to determine association with patient outcome. miR expression was combined with current clinical prognostic factors to develop an enhanced prognostic model in patients with MCL. Results Fourteen miRs were differentially expressed between aggressive and indolent NHL; 11 of 14 were validated in an independent set of NHL (excluding MCL). miR-127-3p and miR-615-3p were significantly associated with overall survival in the MCL training set. Their expression was validated in an independent MCL patient set. In comparison with Ki-67, expression of these miRs was more significantly associated with overall survival among patients with MCL. miR-127-3p was combined with Ki-67 to create a new prognostic model for MCL. A similar model was created with miR-615-3p and Mantle Cell Lymphoma International Prognostic Index scores. Conclusion Eleven miRs are differentially expressed between aggressive and indolent NHL. Two novel miRs were associated with overall survival in MCL and were combined with clinical prognostic models to generate novel prognostic data for patients with MCL.

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

Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network

2016 ◽  
Vol 34 (12) ◽  
pp. 1386-1394 ◽  
Author(s):  
Eva Hoster ◽  
Andreas Rosenwald ◽  
Françoise Berger ◽  
Heinz-Wolfram Bernd ◽  
Sylvia Hartmann ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Risk Stratification ◽  
Mantle Cell Lymphoma ◽  
Growth Pattern ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Low Grade ◽  
Prognostic Impact ◽  
Ki 67 ◽  
Mantle Cell

Purpose Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI. Patients and Methods Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort. Results The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b. Conclusion Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine.

Autologous Stem Cell Transplantation and Addition of Rituximab Independently Prolong Response Duration in Advanced Stage Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 880-880 ◽  
Author(s):  
Eva Hoster ◽  
Bernd Metzner ◽  
Roswitha Forstpointner ◽  
Michael Pfreundschuh ◽  
Lorenz Trümper ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
Response Duration ◽  
Low Grade ◽  
Advanced Stage ◽  
Mantle Cell ◽  
Lymphoma Study Group

Abstract Abstract 880 On behalf of the German Low-Grade Lymphoma Study Group (GLSG) and the European MCL Network Background: In younger patients with mantle cell lymphoma (MCL), autologous stem cell transplantation (ASCT) significantly prolonged response duration with a trend towards improved overall survival in a randomized trial of the European MCL Network (Dreyling et al., ASH 2008). A recently updated clinical trial of the German Low-Grade Lymphoma Study Group (GLSG) also reported a significantly prolonged response duration by the addition of Rituximab to first-line CHOP (Hoster et al., ASH 2008). By pooled analysis of these trials we investigated whether Rituximab and ASCT independently prolong response duration. Methods: The analysis included all advanced stage MCL patients of the trials “CHOP vs. MCP” (Nickenig et al., Cancer 2006), “CHOP vs. R-CHOP” (Lenz et al., JCO 2005) and European MCL trial 1 (Dreyling et al., Blood 2005) with complete or partial remission to either CHOP or R-CHOP first-line induction and randomization between ASCT and Interferon-α maintenance. Response duration was defined as time from the end of successful induction chemotherapy to relapse or death from any cause, overall survival from the end of successful induction chemotherapy to death from any cause. Stratified Kaplan-Meier curves for response duration and overall survival were calculated for the four treatment groups (CHOP without ASCT, CHOP with ASCT, R-CHOP without ASCT and R-CHOP with ASCT). By multiple Cox regression we tested whether the impact of Rituximab (R) and ASCT was independent and additive. Results: One-hundred and eighty patients with MCL were evaluable, 80 treated with R-CHOP, 78 with ASCT (CHOP without ASCT: 56, CHOP with ASCT: 46, R-CHOP without ASCT: 44 and R-CHOP with ASCT: 34). Median age was 55 years (range 34-65), the MIPI classified 71% as low risk, 22% as intermediate risk, and 6% as high risk, and baseline characteristics were comparable between treatment groups. With a median follow-up of 63 months, median response duration was 16 months after CHOP without ASCT, 26 months after R-CHOP without ASCT, 39 months after CHOP with ASCT, and 41 months after R-CHOP with ASCT. In multiple Cox regression including R and ASCT, the hazard ratios of R (0.60, 95% CI 0.42-0.86, p = 0.0056) and ASCT (0.50, 95% CI 0.35-0.70, p = 0.0001) were independently significant. There was no interaction between R and ASCT (p=0.43). Median overall survival was 54 months after CHOP without ASCT, 66 months after R-CHOP without ASCT, 90 months after CHOP with ASCT, and not reached after R-CHOP with ASCT. The hazard ratios for OS were 0.70 (95% CI 0.44-1.12, p = 0.14) for R and 0.63 (95% CI 0.41-0.97, p = 0.0379) for ASCT. Conclusions: Our results indicate an additive effect of ASCT and Rituximab in combination with CHOP on response duration in advanced stage MCL patients and support strategies of several study groups to combine Rituximab-containing induction therapies with ASCT in younger MCL patients. However, even after combined treatment approaches, delayed relapses have been observed, supporting the use of maintenance therapy and the introduction of molecular targeted therapeutical strategies. Disclosures: Hoster: Roche: Travel Support. Off Label Use: Rituximab in Mantle Cell Lymphoma. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees. Dührsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Gisselbrecht:Roche: Research Funding, Speakers Bureau. Unterhalt:Roche: Travel Support. Dreyling:Roche: Honoraria, Research Funding.

scholarly journals Progress in molecular feature of smoldering mantle cell lymphoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Panruo Jiang ◽  
Aakash Desai ◽  
Haige Ye
Keyword(s):  
Mantle Cell Lymphoma ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
Low Frequency ◽  
Molecular Characteristics ◽  
Ki 67 ◽  
Molecular Feature ◽  
Molecular Features ◽  
Mantle Cell ◽  
Low Expression

AbstractMantle cell lymphoma (MCL) is considered one of the most aggressive lymphoid tumors. However, it sometimes displays indolent behavior in patients and might not necessitate treatment at diagnosis; this has been described as “smoldering MCL” (SMCL). There are significant differences in the diagnosis, prognosis, molecular mechanisms and treatments of indolent MCL and classical MCL. In this review, we discuss the progress in understanding the molecular mechanism of indolent MCL to provide insights into the genomic nature of this entity. Reported findings of molecular features of indolent MCL include a low Ki-67 index, CD200 positivity, a low frequency of mutations in TP53, a lack of SOX11, normal arrangement and expression of MYC, IGHV mutations, differences from classical MCL by L-MCL16 assays and MCL35 assays, an unmutated P16 status, few defects in ATM, no NOTCH1/2 mutation, Amp 11q gene mutation, no chr9 deletion, microRNA upregulation/downregulation, and low expression of several genes that have been valued in recent years (SPEN, SMARCA4, RANBP2, KMT2C, NSD2, CARD11, FBXW7, BIRC3, KMT2D, CELSR3, TRAF2, MAP3K14, HNRNPH1, Del 9p and/or Del 9q, SP140 and PCDH10). Based on the above molecular characteristics, we may distinguish indolent MCL from classical MCL. If so, indolent MCL will not be overtreated, whereas the treatment of classical MCL will not be delayed.

scholarly journals Mantle Cell Lymphoma in the Thyroid: A Rare Presentation

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Uzma Mohammad Siddiqui ◽  
Sarika N. Rao ◽  
Pallavi Kanwar Galera ◽  
Nahida Islam ◽  
Mira S. Torres
Keyword(s):  
Flow Cytometry ◽  
Mantle Cell Lymphoma ◽  
Growth Pattern ◽  
Cell Lymphoma ◽  
Case Series ◽  
Low Grade ◽  
Mantle Zone ◽  
Ki 67 ◽  
Mantle Cell ◽  
Zone Growth

Background. While 2% of all extranodal Non-Hodgkin Lymphomas present in the thyroid, there exists insufficient data to describe the incidence of mantle cell lymphoma in the thyroid. A case series of 1400 patients revealed that <1% of thyroid lymphomas may be MCL; hence better understanding of the disease course is essential.Patient Findings. A 65-year-old female was referred for a multinodular goiter. Multiple fine needle aspirations from the dominant right nodule were consistent with Hashimoto’s thyroiditis and flow cytometry was negative. Due to progressing dysphagia, she underwent total thyroidectomy.Summary. Pathology revealed MCL with mantle zone growth pattern in the right thyroid. Flow cytometry showed monoclonal B cells comprising 9% of total cells. The Ki-67 index was 10%. She was diagnosed as having stage IIE MCL and offered conservative management by medical oncology, given that she had no B symptoms.Conclusion. Though chemotherapy is the treatment of choice in MCL, a subset of patients with low-grade disease may be observed. As in our patient, mantle zone growth pattern and a Ki-67 index < 10% suggest a favorable prognosis. A diagnosis of primary MCL in the thyroid remains rare and staging modalities as well as treatment options continue to evolve.

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.

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