Low Grade Lymphoma Study Group Research Articles

Rituximab, gemcitabine and oxaliplatin in relapsed or refractory indolent and mantle cell lymphoma: results of a multicenter phase I/II-study of the German Low Grade Lymphoma Study Group

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005.

Molecular Cytogenetic Profiling Reveals Similarities and Differences Between Localized Nodal and Systemic Follicular Lymphomas.

Recently, we have developed novel highly promising gene expression (GE) classifiers discriminating localized nodal (LFL) from systemic follicular lymphoma (SFL) with prognostic impact. However, few data are available in LFL especially concerning hotspot genetic alterations that are associated with the pathogenesis and prognosis of SFL. A total of 144 LFL and 527 SFL, enrolled in prospective clinical trials of the German Low Grade Lymphoma Study Group, were analyzed by fluorescence in situ hybridization to detect deletions in chromosomes 1p, 6q, and 17p as well as BCL2 translocations to determine their impact on clinical outcome of LFL patients. The frequency of chromosomal deletions in 1p and 17p was comparable between LFL and SFL, while 6q deletions and BCL2 translocations more frequently occurred in SFL. A higher proportion of 1p deletions was seen in BCL2-translocation–positive LFL, compared with BCL2-translocation–negative LFL. Deletions in chromosomes 1p, 6q, and 17p predicted clinical outcome of patients with SFL in the entire cohort, while only deletions in chromosome 1p retained its negative prognostic impact in R-CHOP–treated SFL. In contrast, no deletions in one of the investigated genetic loci predicted clinical outcome in LFL. Likewise, the presence or absence of BCL2 translocations had no prognostic impact in LFL. Despite representing a genetic portfolio closely resembling SFL, LFL showed some differences in deletion frequencies. BCL2 translocation and 6q deletion frequency differs between LFL and SFL and might contribute to distinct genetic profiles in LFL and SFL.

Long-Term Clinical and Molecular Remissions in Patients with Follicular Lymphoma (FL) Following High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)

Background: Long-term clinical and molecular remissions in patients with FL following HDT and ASCT have been evaluated in only a few studies. Results are especially limited for second-line HDT with BEAM (BCNU, etoposide, cytarabine and melphalan). Patients and methods: 73 patients with FL were treated in our institution from 1993 to 2016 (20 1st-line ASCT with total body irradiation (TBI) and cyclophosphamide, 46 2nd-line with BEAM and 8 ≥3rd-line with BEAM). Patients with high-grade transformation before ASCT were excluded. The data were collected retrospectively in 44 and prospectively in 29 patients who participated in two clinical trials: the 1st-line therapy trial of the German Low Grade Lymphoma Study Group (GLSG, principal investigator W. Hiddemann [Lenz G, Blood 2004]) and the salvage therapy LYM1 trial of the EBMT [Pettengell R, JCO 2013]. For the salvage ASCT protocol, most of the patients received 3 - 4 courses of the ESHAP or ICE protocol-since 2001, also usually combined with rituximab. Stem cell apheresis was carried out in the Blood Transfusion Service following these protocols or cyclophosphamide, usually in remission. Patients with partial remission after ASCT received a radiotherapy (RT) with 30-36 Gy in the field of persisting lymphoma, if possible, except participants of the LYM1 trial. Further details are described in an earlier publication of our first 60 patients (Metzner B, Ann Oncol 2013). Response assessment was performed by careful clinical examination (with ultrasound, chest x-ray and partly CT) at regular 3 - 12 monthly time points. In the case of long-term remission (≥ 8 years; n = 26), peripheral blood was tested for minimal residual disease by quantitative t(14;18) RQ-PCR and/or IGH-consensus PCR (n = 25). Results: With a median follow-up of 9.4 years (range 1.2-23.8) 10-year overall survival, progression-free survival and freedom from progression (FFP) after 1st-line ASCT were 80%, 60% and 68%, after 2nd-line ASCT 58%, 37% and 42%, after ≥3rd-line ASCT 50%, 25% and 25%, respectively, with a significant difference for OS, PFS and FFP between 1st-line and ≥3rd-line cohort, for PFS and FFP between 1st- and 2nd-line cohort (p<0.05). The median OS from the initial diagnosis for the 1st-line cohort and the 2nd-line cohort was not yet reached (estimated >23 years); and 9.4 years for the ≥3rd-line cohort; for a subgroup of the 2nd-line cohort with early relapse (time from diagnosis to 1st relapse maximum 24 months, n = 26) not yet reached (estimated >21 years). Ten-year FFP for 2nd-line ASCT and low-risk FLIPI score (n = 16) was 69%, intermediate risk (n = 11) 27% and high risk (n = 18) 29% (p=0.051). No relapses occurred after 8 years following ASCT in 1st or 2nd remission (except one patient 10 years after ASCT). So far, 26 patients developed long-term remissions of at least 8 years (up to 24, median 14 years). 24 of the 25 tested long-term remission patients were MRD-negative at the last follow-up. One patient was MRD-positive (low-level MRD) at the last control (10.6 years after ASCT in 1st line, unchanged as the years before). Five-year non-relapse mortality was 0%. Four of 73 patients developed secondary invasive malignancies in remission after ASCT: in the TBI cohort, 2 of 20 patients; in the BEAM cohort, 2 of 53 patients, (in the 2nd-line ASCT cohort 1 of 45 patients). Conclusion: Sustained long-term clinical and molecular remissions up to > 22 years can be achieved following ASCT in 1st or 2nd treatment line, indicating the potential curative impact of ASCT in FL. [Display omitted] DisclosuresPott:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Long-Term Clinical and Molecular Remissions in Patients with Mantle Cell Lymphoma (MCL) Following High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)

Background:Long-term clinical and molecular remissions in patients with MCL following HDT and ASCT have been evaluated in only a few studies. Results are especially limited for remission duration over 5 years. So the curability of this disease remains an open question. Patients and methods:Altogether 61 patients with MCL were treated in our institution with ASCT from 1998 to April 2019 (50 1st-line ASCT, ten 2nd-line ASCT, one 3rd-line ASCT). The data were collected retrospectively in 29 and prospectively in 32 patients who participated in two clinical trials: the 1st-line therapy trials of the German Low Grade Lymphoma Study Group (GLSG, principal investigator W. Hiddemann [Dreyling M, Blood 2005] and the European Mantle Cell Lymphoma Network [Hermine O, Lancet 2016], respectively. The diagnosis was regularly approved by the reference pathology of the GLSG (W.K.). The induction therapy before 1st-line ASCT consisted of 6 courses CHOP (n=11), mostly combined with rituximab and followed by Dexa-BEAM, and 6 alternating courses of R-CHOP and R-DHAP (n=39), respectively. For the salvage treatment patients usually received three to four courses of the DHAP protocol or the ESHAP protocol, since 2001 also combined with rituximab.Stem cell apheresis was carried out in the Blood Transfusion Service following these protocols in remission. High-dose protocols: 1) total body irradiation with cyclophosphamide or melphalan and cytarabin (n=32) or 2) BEAM (n=29). Patients with partial remission after ASCT received a radiotherapy (RT) with 30-36 Gy in the field of persisting lymphoma, if possible (n=4). Since 09/2016 patients received a maintenance therapy with rituximab after ASCT (every 2 months, planned for 3 years, n=14). Further details are described in an earlier publication of our first 36 patients (Metzner B, Ann Hematol 2013). Response assessment was performed by careful clinical examination and by ultrasound, chest x-ray and partly CT at regular 3 - 12 monthly time points. In the case of long-term remission (≥ 5 years; n = 18), peripheral blood was regularly tested twice a year for minimal residual disease (MRD) by quantitative t(11;14) or allel specific IGH RQ-PCR and/or IGH-consensus PCR.Calculations were done using IBM SPSS Statistics Version 25. Data were analysed as of 01 July 2019. Results:With a median follow-up of 5 years (range 0.1-20) 10-year overall survival, progression-free survival (PFS) and freedom from progression (FFP) after 1st-line ASCT were 54%, 46% and 52%, respectively, after 2nd-line ASCT 42%, 20%and 20%, with a significant difference for PFS (p=0.045) and FFP (p=0.014) between 1st-line and 2nd-line cohort.Further prognostic factors (like sex, age, MIPI, bone marrow involvement, remission grade at ASCT: CR vs. PR, type of HDT: TBI vs. BEAM…) seemed to be without relevance (considering the small subgroups). Only one clinical relapse occurred after 5 years following ASCT in 1stor 2ndremission, respectively (one patient 6 years after 1st-line ASCT and another patient 7 years after 2nd-line ASCT and subsequent radiotherapy). So far, 18 patients experienced long-term remissions of at least 5 years (median 9 years, from 5 to 16 years). Fifteen of 17 tested patients were MRD negative at last follow-up, the two MRD positive patients (positive at a low level below the quantitative measuring range) had no clinical signs of relapse at last follow-up. None of these 18 patients had received rituximab maintenance therapy. None showed clinical criteria of "smoldering mantle cell lymphoma" at induction therapy. Treatment-related mortality at 100 days after ASCT was 1.6% (pneumonitis following TBI). One patient developed a secondary invasive malignancy in remission after ASCT (acute myeloid leukemia 4 years following TBI). Conclusion: Sustained long-term clinical and molecular remissions up to 16 years can be achieved following ASCT (without rituximab maintenance therapy), indicating the potential curative impact of 1st-line ASCT in MCL. The 2nd-line ASCT was obviously less effective. Disclosures Dreyling: Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Acerta: Other: scientific advisory board; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding.

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: A Follow-Up Study of 2 Randomized Trials from the German Low Grade Lymphoma Study Group

Patients with follicular lymphoma (FL) and progression of disease (POD) within 24 months after frontline treatment (POD24) have poor overall survival (OS). The optimal salvage treatment for these patients is unknown. We assessed the role of high-dose therapy and autologous stem cell transplantation (ASCT) in transplant-eligible patients. We analyzed 162 patients with advanced-stage FL who had received frontline treatment within the GLSG1996 or GLSG2000 trials. All patients had POD at age ≤ 65 years and had not received a prior transplant. Second-line treatment was not specified by study protocols. Survival was calculated from time of second-line treatment. Eighteen patients (11%) progressed (n = 16) or died (n = 2) during cytoreductive second-line treatment (considered “cytoreduction failure”); none received ASCT, and their median second-line OS was <1 year. A total of 113 patients had POD24 (70%), whereas 49 had POD after 24 months (30%). Sixty-three patients without cytoreduction failure received ASCT (39%), and 81 received no transplant (50%). In patients with POD24, a significant survival benefit was associated with ASCT with a 5-year second-line progression-free survival for ASCT versus no transplant of 51% versus 19% (hazard ratio, .38; 95% confidence interval, .24 to .62; P < .0001) and a 5-year second-line OS of 77% versus 59% (hazard ratio, .54, 95% confidence interval, .30 to .95; P = .031). Thus, ASCT is an effective treatment option for transplant-eligible patients with high-risk FL as identified by POD24 and should be evaluated in prospective clinical trials.

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.

The composition of the microenvironment in follicular lymphoma is associated with the stage of the disease

The role of regulatory and follicular helper T-cells as prognostic markers in follicular lymphoma was evaluated within the setting of prospective, randomized trials because the previously published results were contradictory. Two hundred sixty-four diagnostic tissue specimens from patients suffering from follicular lymphoma who received therapy within prospective randomized trials of the German Low Grade Lymphoma Study Group were analyzed immunohistochemically for FoxP3 and PD-1 expression to detect regulatory and follicular helper T-cells, respectively. We did not find any correlation between the content of regulatory and follicular helper T-cells and the time to treatment failure or overall survival in patients with advanced stages of follicular lymphoma in need of treatment. However, a perifollicular pattern of regulatory T-cells was associated with a poorer prognosis. The content of regulatory T-cells was positively and the content of follicular helper T-cells inversely correlated with a higher stage of the disease at diagnosis, implying that the microenvironment changes during tumor dissemination. This finding is independent of any therapy administered and needs to be considered when possible biomarkers related to the microenvironment of follicular lymphoma are studied.

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

Low-grade lymphoma: Beyond fludarabine-single therapy

Low-grade lymphoma: Beyond fludarabine-single therapy

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: .

Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma

This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (NHL), in accordance with the licensed indication, based upon the evidence submission from Roche Products Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence included two randomised controlled trials [European Organisation for Research and Treatment of Cancer (EORTC) and German Low Grade Lymphoma Study Group - Fludarabine, Cyclophosphamide and Mitoxantrone and (GLSG-FCM)] comparing the clinical effects of chemotherapy with or without rituximab in the induction of remission at first or second relapse and the clinical benefits of rituximab maintenance therapy versus the NHS's current clinical practice of observation for follicular lymphoma (FL) patients. Both trials showed that in patients with relapsed FL the addition of rituximab to chemotherapy induction treatment increased overall response rates. Furthermore, rituximab maintenance therapy increased the median length of remission when compared with observation only. Safety data from the two trials showed that while the majority of patients reported some adverse events, the number of patients withdrawing from treatment in the EORTC trial was low, with rates not being reported for the GLSG-FCM trial. The most commonly reported adverse events were blood/bone marrow toxicity, skin rashes and allergies. The ERG reran the manufacturer's economic model after altering several of the assumptions and parameter values in order to recalculate the cost-utility ratios, quality-adjusted life-years (QALYs) and estimates of benefits. The manufacturer reported that maintenance therapy with rituximab was cost-effective compared with observation against commonly applied thresholds, with an incremental cost-effectiveness ratio of 7721 pounds per QALY gained. The greatest clinical effectiveness is achieved by R-CHOP followed by rituximab maintenance (R-CHOP>R) and this treatment strategy had the greatest probability of being cost-effective for a QALY of approximately 18,000 pounds or greater. The guidance issued by NICE as a result of the STA states that in people with relapsed stage III or IV follicular NHL, rituximab is now an option in combination with chemotherapy to induce remission or alone as maintenance therapy during remission. Rituximab monotherapy is also an option for people with relapsed or refractory disease when all alternative treatment options have been exhausted.

Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma

This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma (NHL), in accordance with the licensed indication, based upon the evidence submission from Roche Products Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence included two randomised controlled trials [European Organisation for Research and Treatment of Cancer (EORTC) and German Low Grade Lymphoma Study Group – Fludarabine, Cyclophosphamide and Mitoxantrone and (GLSG-FCM)] comparing the clinical effects of chemotherapy with or without rituximab in the induction of remission at first or second relapse and the clinical benefits of rituximab maintenance therapy versus the NHS’s current clinical practice of observation for follicular lymphoma (FL) patients. Both trials showed that in patients with relapsed FL the addition of rituximab to chemotherapy induction treatment increased overall response rates. Furthermore, rituximab maintenance therapy increased the median length of remission when compared with observation only. Safety data from the two trials showed that while the majority of patients reported some adverse events, the number of patients withdrawing from treatment in the EORTC trial was low, with rates not being reported for the GLSG-FCM trial. The most commonly reported adverse events were blood/bone marrow toxicity, skin rashes and allergies. The ERG reran the manufacturer’s economic model after altering several of the assumptions and parameter values in order to recalculate the cost–utility ratios, quality-adjusted life-years (QALYs) and estimates of benefits. The manufacturer reported that maintenance therapy with rituximab was cost-effective compared with observation against commonly applied thresholds, with an incremental cost-effectiveness ratio of £7721 per QALY gained. The greatest clinical effectiveness is achieved by R-CHOP followed by rituximab maintenance (R-CHOP &gt; R) and this treatment strategy had the greatest probability of being cost-effective for a QALY of approximately £18,000 or greater. The guidance issued by NICE as a result of the STA states that in people with relapsed stage III or IV follicular NHL, rituximab is now an option in combination with chemotherapy to induce remission or alone as maintenance therapy during remission. Rituximab monotherapy is also an option for people with relapsed or refractory disease when all alternative treatment options have been exhausted.

Late Effects after Autologous Hematopoietic Cell Transplantation

Over 30,000 autologous hematopoietic cell transplants (HCT) have been performed yearly during the past decade. With improvement in supportive care, few patients succumb to early treatment complications; hence, more attention is being paid to causes of late complications and death. However, interpretation of the data that exist is difficult as the definition of ‘‘late’’ varies by study, as does the patient population, underlying diseases, HCT mobilization and conditioning regimens, stem cell sources, and duration of follow-up (Table 1). Most importantly, the methods used to estimate the incidence of late complications over time are different or are not explained in sufficient detail. Some studies report relative risk or standardized mortality compared with the general population. Other studies report an acturial estimate (which ignores competing risks and thus may overestimate the incidence), whereas others report cumulative incidence calculations.