Grade Lymphoma Study Group Research Articles

MCP (Mitoxantrone/Chlorambucil/Prednisolone) Chemotherapy Impairs the Subsequent Collection of Stem Cells in Comparison to CHOP Induction in Patients with Indolent Lymphomas - Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).

Background: Myeloablative radio-chemotherapy followed by autologous stem cell transplantation (ASCT) significantly prolongs remission duration as compared to interferon alpha maintenance after conventional chemotherapy induction and is a well established treatment option in younger high risk patients with indolent lymphoma. This randomized trial compared the rate of successful stem cell mobilization after initial therapy with either MCP or CHOP in younger patients (< 60 years).Methods: Previously untreated patients with advanced stage indolent lymphoma were randomly assigned to 6 cycles of CHOP or MCP for remission induction. Patients <60 years of age who were subsequently assigned to ASCT received one additional cycle of Dexa-BEAM (dexamethasone, BCNU, etoposide, cytarabine, melphalan) for stem cell mobilization. A minimum of 2x 2.0x106/kg bw CD34+ cells (including back-up) was estimated as appropriate for ASCT. Stem cells were collected and cryopreserved without any purging procedure.Results: According to initial randomization, 45 of 79 patients assigned to ASCT had been treated with CHOP and 34 patients with MCP. 58 (73%) had follicular lymphoma, 13 (16%) mantle cell lymphoma and 8 (10%) lymphoplasmacytic lymphoma. Dexa-BEAM was well tolerated in all patients with a moderate rate of severe infections (13%) or other complications. After CHOP induction, stem cell collection was successfully performed in 42 of 45% cases (93%, 95% CI 82% to 99%). In contrast, stem cell collection was successful in only 15 of 34 patients after MCP chemotherapy (44%, 95% CI: 27% to 62%) (p=0.0003).Conclusions: Initial therapy with MCP significantly impairs the ability to collect stem cells and should be avoided in first line therapy of patients who may qualify for myeloablative consolidation followed by ASCT

Chemotherapy-Free Combination of Obinutuzumab and Ibrutinib in First LINE Treatment of Follicular Lymphoma. the Alternative Study By the German Low Grade Lymphoma Study Group (GLSG)

Chemotherapy-Free Combination of Obinutuzumab and Ibrutinib in First LINE Treatment of Follicular Lymphoma. the Alternative Study By the German Low Grade Lymphoma Study Group (GLSG)

Autologous Stem Cell Transplantation for Patients with Early Progression of Follicular Lymphoma- Retrospective Analysis of 2 Randomized Trials of the German Low Grade Lymphoma Study Group (GLSG)

Background: Follicular lymphoma (FL) is a highly heterogeneous disease. Patients with early progression of disease (POD) have a remarkably poor outcome. Approximately 20% of patients with symptomatic, advanced stage FL experience POD within 24 months of first-line treatment (POD24) and have a 5-year overall survival (OS) of <50%, compared to >85% for patients without POD24 (Casulo et al, JCO 2015; Jurinovic et al, Blood 2016). The optimal salvage treatment for these high-risk patients is unclear. We aimed to assess the role of autologous stem cell transplantation (ASCT) applied as 2nd-line treatment for patients with POD24 who -in principle- qualified for dose-intensified regimens.Methods: Patients with advanced stage FL from 2 successive randomized trials of the German Low Grade Lymphoma Study Group (GLSG1996 [MCP versus CHOP] and GLSG2000 [CHOP versus R-CHOP], followed by randomization for ASCT consolidation versus interferon maintenance, respectively) were eligible for retrospective analysis of 2nd-line treatment if they had progressive, relapsed or refractory FL (ie, less than a partial response), were <65 years, required treatment according to our established criteria, and had not received prior ASCT. Three patients who received an allogeneic transplant (alloTx) as 2nd-line treatment were excluded from this analysis. POD24 was defined as progressive, relapsed or refractory disease within 24 months after 1st-line treatment. Progression-free survival (PFS) and OS were calculated from initiation of 2nd-line treatment (2nd-line PFS and 2nd line-OS, respectively).Results: The evaluable 162 patients were enriched for POD24 (113/162 [70%]). POD24 patients were more likely to receive ASCT as 2nd-line treatment (52/113 [46%] versus 11/49 [22%], p=0.008), whereas rituximab was more commonly added to 2nd-line regimens in patients without POD24 (48% versus 69%, p=0.018). With a median follow-up of 9.4 years, POD24 patients had a significantly shorter 5-year 2nd-line PFS and OS with 35% versus 53% (p=0.04) and 60% versus 83% (p=0.02), respectively, compared to patients without POD24.Within the POD24 group, 52 patients (46%) received ASCT, 54 (48%) received rituximab-containing regimens, 25 (22%) received both ASCT and rituximab as part of their 2nd-line treatment. Patients in the ASCT arm were younger (median age 47 versus 51 years, p=0.018) and more frequently male (73% versus 51%, p=0.026). The distribution of high-risk FLIPI (39% versus 46%, p=0.60), ECOG performance status >1 (10% versus 21%, p=0.15) and the addition of rituximab (48% versus 48%, p=1.0) was not significantly different between the ASCT and no-ASCT groups.In univariate analysis, ASCT for POD24 patients was associated with significantly higher 5-year 2nd-line PFS and OS rates of 51% versus 19% and 77% versus 46% (CI=[35;60]), respectively (Figure). The hazard ratios (HR) for 2nd-line PFS and OS were 0.36 (CI=[0.22;0.59], p<0.0001) and 0.50 (CI=[0.30;0.83], p=0.006).Multivariate analysis demonstrated that ASCT had a stronger impact on favorable treatment outcome compared to the addition of rituximab: the HRs of ASCT for 2nd-line PFS and 2nd-line OS were 0.37 (CI=[0.21;0.63], p=0.0003) and 0.34 (CI=[0.21;0.56], p<0.0001), whereas the HRs of rituximab were 0.63 (CI=[0.39;1.00], p=0.05) and 0.64 (CI=[0.39;1.08], p=0.09), respectively.Finally, to account for the selection bias associated with retrospective studies, we considered patients as ASCT if there had been an attempt to collect an autograft. This included an additional 13 patients from the no-ASCT group and another patient who ultimately received an alloTx as 2nd-line treatment. In this intention-to-treat-like analysis the benefit of ASCT remained statistically significant with a HR=0.48 for 2nd line PFS (CI=[0.30;0.77], p=0.002) and a HR=0.50 for 2nd-line OS (CI=[0.30;0.83], p=0.006).Conclusion: This retrospective analysis suggests that ASCT is an effective 2nd-line treatment option for patients with high-risk FL as defined by the early progression of disease (POD24) who qualify for dose-intensified protocols, and should be evaluated in prospective clinical trials. It remains to be determined if ASCT is also an effective 1st-line treatment strategy for selected patients identified to be high-risk by pre-treatment risk classifiers, such as the recently established clinicogenetic risk-model m7-FLIPI. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Evaluation Of Myeloablative Therapy Followed By Autologous Stem Cell Transplantation In First Remission In Patients With Advanced Stage Follicular Lymphoma After Initial Immuno-Chemotherapy (R-CHOP) Or Chemotherapy Alone: Analysis Of 940 Patients Treated In Prospective Randomized Trials Of The German Low Grade Lymphoma Study Group (GLSG)

BackgroundThe anti-CD20 antibody rituximab has dramatically changed the treatment paradigms for advanced stage follicular lymphoma (FL) and has improved overall survival. The question whether myeloablative treatment followed by autologous stem cell transplantation (ASCT) in first remission may add further benefit in the era of initial rituximab-chemotherapy induction remains currently unsolved. MethodsWe report on the long-term outcome of 940 patients, randomized for treatment with ASCT versus IFN-alpha maintenance in first remission after initial therapy with MCP, CHOP or R-CHOP in two consecutive randomized trials for patients with advanced stage FL of the GLSG . ResultsA total of 472 patients, (38 with initial MCP therapy, 199 with initial CHOP therapy and 224 with initial R-CHOP therapy, 13 not documented), were randomized to receive ASCT. The remaining 468 patients were randomized for IFN-maintenance (39 with MCP, 201 with CHOP and 219 with R-CHOP, 7 not documented). The patient characteristics, the initial therapy and the quality of remission were well balanced between ASCT and IFN-maintenance. After a median follow up of 8.3 years 454 pts randomized for IFN-maintenance and 445 pts randomized for ASCT were evaluable for treatment failure. The estimated failure free survival at 10 years was 32% (95% CI 0.26-0.37) for IFN-alpha maintenance and 51% (95% CI 0.45-0.57) for ASCT. For patients assigned to CHOP or MCP (no rituximab during induction) the estimated failure free survival after 10 years was 18% for IFN-maintenance and 45% for ASCT (hazard ratio 0.49, 95% CI 0.39-0.61). Among the 423 evaluable patients assigned to R-CHOP the estimated failure free survival at 10 years was 53% for IFN-maintenance and 58% for ASCT (hazard ratio 0.77, 95% CI 0.56-1.07). ConclusionsAfter a median follow up of more than 6 years in 423 patients assigned to R-CHOP, only a small improvement in time to treatment failure could be observed for ASCT compared to IFN-alpha maintenance. This is in strong contrast to patients treated with chemotherapy only (figure 1). The promising results for ASCT observed in the pre-rituximab era cannot be confirmed after initial immuno-chemotherapy. Since the use of ASCT is hampered by relevant toxic side effects, the actual data suggest that ASCT for patients with follicular lymphomas in first line therapy is of questionable benefit. [Display omitted] Disclosures:Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hoster:Roche: Honoraria, Travel Support Other. Unterhalt:Roche: Travel Support Other.

Treatment of Early Stage Nodal Follicular Lymphoma Using Involved-Field Radiotherapy and Rituximab: Preliminary Results of the Mir Trial (phase II study of the German Low Grade Lymphoma Study Group (GLSG))

AbstractAbstract 1634 Background:The commonly recommended treatment for early stage follicular lymphoma grade 1 or grade 2 (stage I/II) is involved-field radiotherapy (IF RT). However, a prospective German trial showed improved progression free survival compared to historical data using large field radiation techniques as extended-field radiotherapy or total lymphatic irradiation (Stuschke et al, Cancer, 80, 1997). This trial led to the conclusion that large volume radiation techniques may prevent relapses of microscopic lymphatic disease and is confirmed by the a new study, which was presented at Lugano 2011 (Engelhard et al., Ann Oncol, 22 Suppl4, 2011). However, those extensive radiation protocols are associated with significant toxicities, especially grade 3 and grade 4 adverse events concerning the hematopoietic system. It has been shown that the CD20 antibody Rituximab also has an anti lymphoma activity in CD20 positive follicular lymphoma. It might prevent out field recurrences in case of involved field radiotherapy. The German Low Grade Lymphoma Study Group (GLSG) and the German Radiation Oncology Group (ARO) of the German Cancer Society conducted a prospective, multicenter phase II trial investigating the efficacy and toxicity of a combined involved-field radiotherapy in combination with Rituximab treatment (MIR = MabThera and Involved field Radiotherapy) with an accrual of 85 patients (ClinicalTrials.gov Identifier: NCT00509184). Patients and Methods:85 patients (47 male / 38 female) with early stage CD20 positive follicular lymphoma grade 1/2 were included in the trial at 16 German centers between February 2007 and October 2010. Median age at diagnosis was 55 years (21–75 years). Stage I disease was diagnosed in 48 patients and Stage II in 37 patients. Macroscopically left lymphoma after diagnostic surgery was observed in 55 patients, no macroscopic lymphoma in 26 patients and an equivocal status (e.g. due to postoperative tissue changes) in 4 patients. The treatment included a first block of Rituximab (4 weekly cycles; 375 mg/m2body surface), a 4 week treatment gap with a restaging CT / planning CT of the involved region in week 7 and followed by another block of Rituximab(4 weekly cycles) concurrently with an IF RT of 40 Gy for macroscopic tumor or 30 Gy in case of a complete remission (CR). The fractionation schedule was 5×2Gy per week. Primary endpoint of the study was progression free survival (PFS) at 2 years. Secondary endpoints were CR rate after Rituximab monotherapy (week 7) and after complete treatment (week 18). Additional endpoints were relapse rate, relapse pattern, overall survival, toxicity and quality of life. The protocol was approved by the ethics committee of the University of Heidelberg Medical School and the Paul-Ehrlich-Institute (PEI-registration number 432/06). The trial was in accordance to the Declaration of Helsinki. Recruitment was finished in October 2010. Clinical report form (CRF) collection is currently under way. Results:The treatment was well tolerated. There were 16 serious adverse events (SAE; toxicity grade 3 or higher): 3 infections, 1 hypersensitivity, 2 cardiac disorders, 1 vascular disorder, 1 respiratory disorder, 2 gastrointestinal disorders, 4 bone injuries. Two patients died due to secondary neoplasm. 3/16 were considered to be related to the treatment. Eight patients had to be excluded from the primary response evaluation due to failed inclusion criteria (e.g. stage, histology.) or early withdrawal of their consent. The mean follow-up of the remaining 78 patients has been 22.3 +/− 11.4 months, so far. Of 55 patients with remaining macroscopic lymphoma at inclusion, 26% showed a CR at week 7 after 4 cycles Rituximab (15% missing, CRF data still have to be collected). The CR rate improved to 60% at week 18 at the first follow-up examination at week 18 (15% of data still missing) and to 80% at month 6 (22% of data still missing). A total of 8 relapses have been detected (1 infield relapse) so far. The 2 years actuarial progression free survival and overall survival has been estimated to be 90% and 96%, respectively. Conclusion:The combination of Rituximab and IF RT in early stage nodal follicular lymphoma grade 1/2 is well tolerated and shows promising initial results. So far, 2 years PFS matches with that of large field radiotherapy without the accompanying toxicity and is superior to historic data of IF RT only. Disclosures:Herfarth:Roche: Honoraria, Research Funding. Borchmann:Roche: Honoraria, Research Funding. Budach:Roche: Honoraria. Viardot:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Witzens-Harig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Support of (other) clinical trials and Scientific Advisory Boards Other.

Consolidative therapy with stem cell transplantation improves survival of patients with mantle cell lymphoma after any induction regimen

Intensive induction regimen followed by high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) is frequently used to improve outcomes in patients with mantle-cell lymphoma. The comparative impact of conventional vs intensive induction regimen before transplantation is unknown. Forty-eight patients with mantle-cell lymphoma receiving SCT at our institution between January 2000 and December 2010 were included in this study. At the time of initial presentation, 43 (89.5%) had stage IV disease and 18 (37.5%) received more than one chemotherapy regimen before transplantation. Forty patients underwent auto-SCT and 7 had allogeneic SCT (allo-SCT); 1 patient had an allo-SCT for relapsed disease after auto-SCT. At the time of this analysis (median follow-up of 6 years from diagnosis and 4 years from transplantation), 40 patients (88%) were alive with a 5-year disease-free survival of 74.8%. Age, disease stage, number of regimens pre-SCT, pre-SCT disease status, and type of SCT had no impact on long-term outcomes. Importantly, there were no differences among the types of induction regimen on outcomes in this cohort receiving SCT. Based on our data, we believe that future studies should focus on strategies to prevent disease relapse rather than comparing induction regimens before stem cell transplantation.

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The Annual Meeting of the American Society of Clinical Oncology, June 4–8, 2010; Chicago, IL

Induction with rituximab-based immunochemotherapy has considerably improved survival outcomes in patients with poor prognosis follicular lymphoma (FL) in both the first-line and relapsed/refractory disease settings. 1 Sousou T Friedberg J Rituximab in indolent lymphomas. Semin Hematol. 2010; 47: 133-142 Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar However, FL remains incurable and approaches to improve response duration and prolong survival have included evaluation of strategies using rituximab (R-maintenance). In the relapsed/refractory setting, a number of studies have investigated different R-maintenance schedules following various chemotherapy or rituximab-based immunochemotherapy induction strategies. 2 Forstpointner R Unterhalt M Dreyling M et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006; 108: 4003-4008 Crossref PubMed Scopus (420) Google Scholar , 3 Van Oers MH Van Glabbeke M Giurgea L et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010; 28: 2853-2858 Crossref PubMed Scopus (267) Google Scholar , 4 Pettengell R Schmitz N Gisselbrecht C et al. Randomized study of rituximab in patients with relapsed or resistant follicular lymphoma prior to high-dose therapy as in vivo purging and to maintain remission following high-dose therapy. J Clin Oncol. 2010; 28 (abstract 8005).: 574s Google Scholar , 5 Landgren O Dunleavy K Wilson WH Re: Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009; 101 (author reply 89–90.): 1287-1288 Crossref PubMed Scopus (4) Google Scholar Several of these trials have reported prolonged median progression-free survival (PFS) compared to observation. However, the study by Van Oers et al failed to show an overall survival (OS) benefit, and the conclusions drawn from a meta-analysis that indicated R-maintenance to yield improved OS have been viewed with caution. 3 Van Oers MH Van Glabbeke M Giurgea L et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010; 28: 2853-2858 Crossref PubMed Scopus (267) Google Scholar , 6 Vidal L Gafter-Gvili A Leibovici L et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009; 101: 248-255 Crossref PubMed Scopus (145) Google Scholar

Rituximab Overcomes Sex as a Strong Adverse Prognostic Factor for Treatment Outcome in Patients with Follicular Lymphoma: Analysis of Patients Treated with Rituximab/CHOP or CHOP in Randomized Trials of the German Low Grade Lymphoma Study Group (GLSG).

Abstract 3706Poster Board III-642Sex has been recognized as an important prognostic factor for the treatment outcome of patients with lymphoma. Thus, several retrospective analyses have shown that male sex is associated with an inferior outcome in advanced stage follicular lymphoma. This was confirmed in a retrospective analyses of 1795 patients with follicular lymphoma using Cox regression analysis, in which male sex was independently associated with inferior survival (Solal-Celigny et al., Blood 2004). We now analyzed the prognostic impact of sex on treatment outcome of 1172 patients with follicular lymphoma treated first line with CHOP or R-CHOP in prospectively randomized clinical trials of the German Low-Grade Lymphoma Study Group (GLSG). From these, 616 pts were treated with CHOP, 556 pts with R-CHOP. FLIPI was equally distributed between the two treatment arms (low risk 14% vs. 14%, intermediate risk 42% vs. 41% and high risk 44% vs. 45 %, respectively). 48% of the patients were male (50% in the CHOP and 46% in the R-CHOP arm). For all patients there was a significantly inferior time to treatment failure (TTF) for male patients with a median of 43 months compared to 61 months for female patients (p=0.0035). In the patient group treated with CHOP alone the median TTF was 30 months for male vs. 40 months for female patients (p=0.0041). The observation that male sex was associated with inferior treatment outcome was seen both in the elderly (above 60 yrs of age) as well as the younger patient group (below 60 yrs of age). However, after treatment with R-CHOP sex did not affect treatment outcome anymore with virtually the same results in male vs. female patients (for the total group and for patients < 60yrs TTF median not reached in both arms, p = n.s.; for pts > 60 yrs TTF 81 vs. 84 months, respectively, p=n.s.). In multivariate analysis, also adjusting for FLIPI risk factors, male sex showed up as an independent prognostic factor for patients treated with CHOP alone (HR 1.82; 1.32 – 2.5; p=0.0002), but not for patients treated with R-CHOP (HR 1.06; 0.68 - 1.66, p = 0.79; p=0.0476 for the interaction term of sex with Rituximab). Based on this, male patients had the highest benefit when rituximab was added to CHOP (R-CHOP vs. CHOP: male pts HR 0.31,0.21 - 0.46, p<0.0001 and female pts. HR 0.53, 0.37 - 0.76, p = 0.0005). These data demonstrate that Rituximab functions as an equalizer with regard to sex as a prognostic factor and underlines that well established prognostic factors may lose their predictive power with the emergence of novel effective treatment approaches. Disclosures:Buske:Roche: Honoraria. Hoster:Roche: travel support. Dreyling:Roche: Honoraria, Research Funding. Hallek:BayerScheringAG: Honoraria, Research Funding. Hiddemann:Roche: Honoraria, Research Funding. Unterhalt:Roche: .

Autologous Stem Cell Transplantation after Myeloablative Therapy in First Remission May Be Beneficial in Patients with Advanced Stage Follicular Lymphoma after Front-Line Therapy with R-CHOP. An Analysis of Two Consecutive Studies of the German Low Grade Lymphoma Study Group (GLSG)

The addition of Rituximab (R) to front-line combination chemotherapy has substantially improved the long term perspectives of patients with advanced stage follicular lymphoma (FL) resulting in median progression free survival (PFS) times of more than 36 months. In this situation the potential role of myeloablative herapy with subsequent autologous stem cell transplantation (ASCT) in 1st remission needs to be critically reassessed. For this purpose two consecutive studies of the GLSG were analyzed both randomizing in 1st remission for Interferon alpha (IFN) maintenance therapy versus ASCT. In the GLSG trial ‘96 initial therapy comprised a randomized comparison of CHOP versus Mitoxantrone, Chlorambucil and Prednisone (MCP) (total patient number 312) while in GLSG study ‘00 CHOP was randomly compared to R-CHOP (total patient number 268). Hence, both studies had an identical treatment arm of CHOP followed by either IFN maintenance or ASCT. In both studies, the identical treatments revealed superimposable results with a 5 years PFS of 27% after CHOP and IFN maintenance and 66% after CHOP followed by ASCT. Taking these data as internal control R-CHOP followed by IFN maintenance achieved a 5 year PFS of 67% which is hence comparable to CHOP followed by ASCT. R-CHOP followed by ASCT, however, revealed a 5 year PFS of 79% with only one relapse after 24 months. [Display omitted] Although the difference between R-CHOP followed by IFN maintenance or ASCT is currently not yet significant it strongly suggests a beneficial effect of ASCT in the era of R-CHOP front-line therapy particularly for intermediate of high risk patients with advanced stage FL.

Impact of Autologous Stem Cell Transplantation and/or Rituximab on Outcome of Patients with Relapsed Follicular Lymphoma- Retrospective Analysis of 2 Randomized Trials of the German Low Grade Lymphoma Study Group (GLSG).

Background: There is no standard therapeutic approach for patients (pts) with relapsed advanced stage follicular lymphoma (FL). The impact of high-dose therapy followed by autologous blood stem cell transplantation (ASCT) with or without addition of rituximab (R) to salvage regimens was evaluated.Methods: Patients with advanced stage FL from 2 successive prospective randomized trials of the GLSG (MCP vs. CHOP and CHOP vs. R-CHOP, both followed by randomization for IFN maintenance vs. ASCT) were eligible for retrospective analysis of subsequent therapy if they had progressive, relapsed or refractory disease following 1st line treatment, were <65 years, had no prior ASCT and required treatment according to our established criteria.Results: 222 patients were identified of whom 167 data sets were available for analysis (n=36 lost to follow-up, n=6 dead before initiation of salvage therapy, n=13 no indication for treatment). Median age was 50 years (range 19–64), 97 pts (58%) were male, 20 pts (12%) had previously received R (R-CHOP 1st line). 87 pts (53%) were treated with a R-containing salvage regimen. Most commonly used chemotherapy protocols were purin-analogue based (26%), followed by alkylator (22%) and anthracycline (13%) based regimens. Overall response rate (ORR) for chemotherapy with or without R 2nd line was 86% (CR 39%, PR 47%) and 78% (CR 26%, PR 52%), respectively. Median PFS for pts treated with or without Rituximab 2nd line was 3.4 and 2.8 years (yrs), median OS 8.3 and 7.2 yrs, respectively. Adequate numbers of peripheral blood stem cells could be harvested in 92% of evaluable patients. 66 pts received ASCT (40%) of whom 31 were also treated with R. 26 pts (39%) received a TBI-containing conditioning therapy. Most common non-hematologic grade 3/4 toxicity of ASCT were mucositis (43%) and infectious complications (30%). 4 pts died within 3 months after ASCT (6%). ORR before and after ASCT was 79% (CR 19%, PR 60%) and 95% (CR 60%, PR 35%), respectively. Median PFS for pts receiving ASCT or not was 5.5 and 2.3 yrs (p=0.038), median OS 7.2 yrs and not reached yet, respectively.Conclusion: This retrospective analysis of two prospective multicenter trials suggests that patients with relapsed FL qualifying for ASCT may profit from that approach in terms of improved response rates and prolonged remission duration, albeit with more toxicity and an early death rate of 6%. Subgroup analysis revealed that the addition of R to salvage therapy primarily benefited patients not receiving ASCT 2nd line. Comparison of these results with ASCT in 1st remission with or without R is ongoing and will be presented at the meeting.

Rituximab in Combination with CHOP in Patients with Follicular Lymphoma: Analysis of Treatment Outcome of 552 Patients Treated in a Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG) after a Follow up of 58 Months

We have previously reported that compared to CHOP alone the addition of Rituximab (R) to CHOP significantly increases the response rate (RR), the time to treatment failure (TTF) and also the overall survival (OS) in patients with newly diagnosed advanced follicular lymphoma. However, in the previous report, the median observation time was short with 18 months and no data were reported on the outcome of different risk groups according to the FLIPI (Hiddemann et al., Blood 2005). We now report on the treatment outcome of 552 patients with advanced stage follicular lymphoma randomized between R-CHOP versus CHOP alone after a median follow up of 58 months. Responding patients < 60 yrs. of age underwent a second randomization in first remission for Interferon alpha maintenance (IFN) versus myeloablative radio-chemotherapy with subsequent stem cell transplantation (ASCT), whereas all older pts received IFN maintenance.R-CHOP induced a significantly higher RR (97% vs. 91%, p=0.005). Furthermore immunochemotherapy resulted in significantly longer TTF (median not reached vs. 35 months, 5-years TTF 65% vs. 32%, p<0.0001), response duration (RD, 5-years RD 66% vs. 35%, p<0.0001), and OS (5-years OS R-CHOP 90% vs. CHOP 84%, p = 0.0493). To analyse the impact of R-chemotherapy in different risk groups we performed subgroup analyses for patients with low (LR), intermediate (IR) or high risk (HR) according to the FLIPI: R-CHOP prolonged significantly TTF in all risk groups compared to CHOP alone (5-years TTF: 84% vs. 46% for LR (p=0.0021); 73% vs. 37% for IR (p<0.0001); 49% vs. 23% for HR (p<0.0001). The superiority of R-CHOP vs. CHOP could be documented in the patient group not treated with ASCT: the RD was significantly prolonged by the immunochemotherapy (5-years probability 62% vs. 26%, respectively; p<0.0001). This could not be seen in the group of younger patients consolidated with ASCT (5-years probability 78% vs. 66%, p=0.43). However, the number of events was too low to draw any final conclusion.These data with a mature follow-up demonstrate that first–line R-CHOP significantly improves response rate and TTF in patients with FL compared to the respective chemotherapy alone. However, they also demonstrate that R-chemotherapy might be not sufficient for a long-lasting improvement. This indicates the necessity to perform clinical trials that test whether adding consolidation and/or maintenance after initial cytoreduction further improves treatment outcome.

Allogeneic Stem Cell Transplantation with Dose-Reduced Conditioning in Relapsed Follicular and Mantle Cell Lymphoma - A Prospective Phase II Trial of the German Low Grade Lymphoma Study Group (GLSG).

Background: Conventional therapy achieves high initial response rates in follicular (FL) and mantle cell lymphoma (MCL), but even after introduction of combined immuno-chemotherapy, a continuous relapse pattern has been observed. The introduction of dose-reduced conditioning prior to allogeneic peripheral blood stem cell transplantation significantly reduced early treatment-associated toxicity of this curative approach. In 2003, the German Low Grade Lymphoma Study Group initiated a prospective phase II trial to investigate the feasibility and efficacy of this approach in a multi center approach.Methods: Patients with a high risk profile (bulky disease, 3 lymph nodes >3 cm, elevated LDH, >20% bone marrow infiltration, hematopoietic insufficiency) received a conventional salvage chemotherapy, e.g. 2–4x (R-)FCM. Subsequently, all patients received a dose-reduced conditioning (30 mg/m2 fludarabine d-7-4, 30 mg/m2 cyclophosphamide d-4-3) and an optional low dose TBI (2–4 Gray, d-8). Immunosupression consisted of ATG-Fresenius (10mg/m2 bs d-3-1 if unrelated donor), cyclosporine A starting day −1 and mycophenolat (2× 15mg/kg). If T-cell chimerism was established after discontinuation of immunosuppression, donor lymphocyte infusion was applied on days +120, +150 and +180 with increasing doses (2× 105–107/kg) in cases of persistent lymphoma.Results: After a median follow-up of 17 months, a total of 32 patients are evaluable (21 FL and 11 MCL). Median age was 48.5 years (34–62) with a median of 3 prior therapies (1–8). Eigth patients had a family donor and 24 were transplanted from an unrelated donor (no mismatch in 25 and 1 mismatch in 8 cases). 2 early infectious deaths were observed at day 30 and 87 resulting in a treatment-associated mortality (d100) of 6% and another death after 1014 days. After 2 years follow-up, failure-free and overall survival rates were 73% and 77%, respectively. As expected, failure-free survival rates differed significantly between FL (80%) and MCL patients (60%).Discussion: This multicenter trial confirms allogeneic stem cell transplantation with dose-reduced conditioning achieving long-term remissions especially in patients with relapsed FL with rather low mortality. Thus, in younger high risk patients, this therapeutic option should be discussed in relapsed disease. Randomized or case-control trials are warranted to exactly define the role of allogeneic transplantation in FL and MCL.

High anti-lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A multicenter phase II study of the German Low Grade Lymphoma Study Group (GLSG)

On the basis of a preceding phase I study, the current trial explored bendamustine in combination with mitoxantrone and rituximab (BMR) in patients with stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL) with or without prior rituximab containing chemo-immunotherapy (R-chemo) treatment. Therapy consisted of bendamustine 90 mg/m2 days 1 + 2, mitoxantrone 10 mg/m2 day 1, rituximab 375 mg/m2 day 8. Treatment was repeated on day 29 for a total of four cycles. Between 3 April and 04 July, 57 patients were recruited from 24 participating institutions, 39% of whom had received prior R-chemo therapy. Median age was 66 years (40 – 83). Lymphoma subtypes were 29 follicular (FL), 18 MCL, and 10 other indolent lymphomas. The overall response rate (ORR) was 89% with 35% CR and 54% PR. ORR in R-chemo pretreated patients was 76% (38% CR, 38% PR). After a median observation time of 27 months (1 – 43), the estimated median progression free survival is 19 months. The 2 year overall survival is 60% for patients with FL and MCL. Treatment related toxicities of grade 3/4 comprised a reversible myelosuppression (10% anemia, 78% leukocytopenia, 46% granulocytopenia, 16% thrombocytopenia). However, unexpected hospitalisations were necessary after 4% of BMR-application only. BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory FL, MCL and other indolent lymphomas.

Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG)

AbstractIn follicular lymphoma (FL) and mantle cell lymphoma (MCL) the monoclonal antibody rituximab (R) improves the prognosis when combined with chemotherapy. The present study investigated R-maintenance after R-chemotherapy. Patients with recurring or refractory FL and MCL were randomized to 4 courses of fludarabine, cyclophosphamide, and mitoxantrone (FCM) alone or combined with R (R-FCM). Responding patients underwent a second randomization for R-maintenance comprising 2 further courses of 4-times-weekly doses of R after 3 and 9 months. The first randomization was stopped after 147 patients, when R-FCM revealed a significantly better outcome. All subsequent patients received R-FCM. Of the 176 patients who are currently evaluable (as of October 2005), 138 received R-FCM for remission induction. Response duration was significantly prolonged by R-maintenance after R-FCM, with the median not being reached in this evaluation versus an estimated median of 16 months (P = .001). This beneficial effect was also observed when analyzing FL (P = .035) and MCL (P = .049) separately. Hence, R-maintenance is effective after salvage with R-chemotherapy and significantly prolongs response duration in patients with recurring or refractory FL or MCL.

Rituximab Is the Essential Treatment Modality That Underlies the Significant Improvement in Short and Long Term Outcome of Patients with Advanced Stage Follicular Lymphoma - A 10 Year Analysis of GLSG Trials.

Recent reports have shown a significant improvement of overall survival (OS) in patients with advanced stage follicular lymphoma (FL) over the last few decades. In order to identify the essential treatment modalities that underlie these observations two consecutive study generations of the German Low Grade Lymphoma Study Group (GLSG) covering a ten year period were analyzed for remission rates (RR), time to treatment failure (TTF) and OS. The analysis was adjusted for risk factors using the FLIPI, and type of primary induction therapy (including Rituximab or not). Between 1996 and 2005 complete data sets of 1332 patients with stage III or IV FL who were in need of therapy were collected. Therapy comprised prospective randomized comparisons of CHOP versus MCP in GLSG study '96 (1996 – 2000) and CHOP versus R-CHOP in GLSG study '00 (1996 – 2005). The entry criteria and the distribution of risk factors were identical in both study generations. The type of chemotherapy had limited impact on RR with CHOP being superior to MCP (86% versus 77%, p=0.0094) but no impact on TTF or OS. Patients treated in GLSG '00 had a significantly better RR (94% versus 88%, odds ratio 0.47, p=0.0002), a longer TTF (median 48 months versus 32 months, relative risk 0.66, p<0.0001) and a longer OS (89% versus 78% at four years, relative risk 0.42, p<0.0001) as compared to patients of GLSG '96. Multiple Cox regression analysis revealed Rituximab as being the determinant responsible for the differences in RR (adjusted odds ratio 0.45, p<0.0001) and TTF (adjusted relative risk 0.39, p<0.0001). With regard to OS, after adjusting for Rituximab as most relevant determinant (adjusted relative risk 0.44, p = 0.0064), the difference between the study generations still remained significant (adjusted relative risk 0.57, p = 0.0071). Hence, Rituximab is the essential treatment modality that underlies the improvement in short and long term outcome of patients with advanced stage FL. Most probably, more effective salvage therapy with Rituximab containing combinations account also for the additional improvement in OS.

Front - Line Combined Immuno-Chemotherapy (R-CHOP) Significantly Improves the Time to Treatment Failure and Overall Survival in Elderly Patients with Advanced Stage Follicular Lymphoma - Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).

Follicular lymphoma (FL) is an indolent disease of the advanced age with more than 40 % of the patients being older than 60 years at diagnosis and an age-specific incidence peaking above 75 years. We now analyzed the treatment outcome of elderly patients in the GLSG multicenter phase III study comprising a prospective randomized comparison of R-CHOP versus CHOP alone in patients with advanced stage FL. 221 patients > 60 years with untreated FL were randomized for therapy with R-CHOP (R-CHOP: Rituximab 375 mg/m2 d0–1; cyclophosphamide 750 mg/m2 d1; doxorubicine 50 mg/m2 d1; vincristine 1.4 mg/m2 d1; prednisone 100 mg/m2 d1–5) (n=109) or CHOP alone (n=112). Patient characteristics were well balanced between the treatment groups, also with regard to the distribution of the FLIPI risk groups (≥ 3 adverse factors 73% and 66 % in the R-CHOP and CHOP arm, respectively). R-CHOP induced higher overall response rates and significantly prolonged the time to treatment failure (TTF)(median 5.0 years versus 2.1 years, respectively; logrank test: p<0.0001) compared to CHOP in the elderly patient group. Furthermore, the estimated 4-years progression free survival was 62.2% for R-CHOP versus 27.9 % after CHOP (logrank: p< 0.0001). Importantly, R-CHOP was able to prolong the overall survival in elderly patients compared to CHOP with an estimated 4-years overall survival of 90% after immunochemotherapy versus 81 % after CHOP alone (logrank test: p=0.039). In the multivariate analysis individual FLIPI risk factors such as elevated serum LDH level, a hemoglobin level below 12 g/dl, the number of nodal areas (> 4) as well as application of CHOP alone were independently associated with a shorter TTF. Treatment related side effects were similar in both patient groups and comprised predominantly myelosuppression. In summary, the addition of Rituximab to CHOP significantly improves the outcome of elderly patients with previously untreated advanced stage FL without adding major side effects.

A New Prognostic Index (MIPI) for Patients with Advanced Stage Mantle Cell Lymphoma.

On behalf of the German Low Grade Lymphoma Study Group (GLSG) and the European MCL Network.Background: There is no generally established prognostic classification system for patients with mantle cell lymphoma (MCL), as the International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI) have been developed based on data of patients with diffuse large cell and follicular lymphoma, respectively.Methods: The data of 455 patients with advanced stage MCL treated first-line within three clinical trials of GLSG and European MCL Network have been analyzed to clarify the prognostic relevance of IPI and FLIPI and to derive a new prognostic index of overall survival (OS). Age, sex, ECOG performance status, Ann Arbor stage, B-symptoms, number of extranodal sites, number of involved nodal areas, tumor size, serum LDH activity, WBC count, platelet count, hemoglobin, albumin, β2-microglobulin and cell proliferation (Ki-67) were considered as candidate prognostic factors. Statistical methods included Kaplan-Meier estimates and logrank test for the validation of IPI and FLIPI and multiple Cox regression with backward variable selection for the derivation of the new prognostic index.Results: IPI showed a significant impact on OS, but low-intermediate and high-intermediate risk groups comprised more than two thirds of the patients and were not well separated. According to the FLIPI, only 6% of the patients were classified as low risk and almost two thirds of the patients as high risk, and low and intermediate risk groups were not separated. Four of the candidate prognostic factors were independently associated with OS, namely age, ECOG performance status, LDH and WBC count. The relative risk was 1.42 (95% confidence interval 1.18 to 1.72, p = 0.0002) for an increased age by ten years, 2.01 (1.19 to 3.39, p = 0.0088) for an ECOG greater than one, 1.51 (1.13 to 2.02, p = 0.0059) for a 2 fold elevation of LDH and 2.56 (1.66 to 3.95, p < 0.0001) for a 10 fold increase of WBC count. According to these four parameters, patients could be classified into a low risk (44% of the patients, median OS not reached), an intermediate risk (35%, median OS 51 months), and a high risk group (21%, median OS 29 months).Discussion: IPI and FLIPI showed only modest prognostic discrimination in our external validation data set of patients with advanced stage MCL. In contrast, age, ECOG performance status, LDH and WBC were identified as independent prognostic factors of OS, and three reasonably sized and well separated risk groups were defined. With four clinical prognostic factors readily determined in clinical routine, our new prognostic index (MIPI) is superior to the IPI. Bootstrap validation confirmed the separation of three risk groups, but external validation is still needed. The MIPI may prove to be an important tool to facilitate risk-adapted treatment decisions for patients with advanced stage MCL.

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)

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. &gt;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]