Rituximab Consolidation Research Articles

Interim analysis of the largest prospective trial to date in adult CD20-positive post-transplant lymphoproliferative disorder (PTLD): Introducing risk-stratified sequential treatment (RSST).

8030 Background: The prospective, multicenter international phase II PTLD-1 trial of sequential treatment (ST, 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF) in adult CD20-positive PTLD demonstrated excellent efficacy (90% overall response rate, ORR) and safety (11% treatment-related mortality, TRM). As the response to rituximab predicted overall survival (OS), the trial was amended in 2007 introducing risk-stratified sequential treatment (RSST) according to the response to rituximab (NCT00590447). Methods: Following rituximab on days 1, 8, 15 and 22, RSST consisted of 4 3-weekly courses of rituximab monotherapy for patients (pts) in complete remission (CR, low risk) while all others (high risk) received 4 cycles of R-CHOP-21 + G-CSF. Key exclusion criteria were CNS involvement, HIV infection, severe organ dysfunction not related to PTLD, and ECOG > 2. Primary endpoint was ORR. This is an analysis of the first 91 patients treated with RSST. Results: 79/91 pts had monomorphic, 12 polymorphic PTLD. 41/91 pts were kidney, 27 liver, 12 heart, 7 lung or heart+lung, 3 heart+kidney and 1 kidney+pancreas transplant recipients. Median age at diagnosis was 60 years (range 20-82). 73/91 pts had late PTLD and 39/85 PTLDs were EBV-associated. 1 pt died before initiation of treatment; 5 pts discontinued treatment after 4 cycles rituximab. TRM of RSST was 7/90 (8%) including 5 deaths with unknown remission status. ORR was thus 74/80 (93%, 95%CI: 84-97%; CR: 62/80 [78%]). 24/90 pts (27%) achieved CR with 4 cycles of rituximab. After a median follow up of >3 years, relapse rate in low risk pts was not increased by rituximab consolidation in RSST compared to CHOP consolidation in ST (3/23 vs. 5/14, p=0.104]). In patients in PD after rituximab, R-CHOP was more effective than CHOP in achieving CR (15/23 vs. 3/11, p=0.038). OS at 3 years was higher with RSST (70%, 95% CI: 60-82%) compared to ST (61%, 95%CI 49-72%) but this difference was not significant. Conclusions: With RSST 27% of pts were classified as low risk and achieved durable tumor control without chemotherapy while R-CHOP seems more efficient than CHOP in in high risk patients.

Brief Chemoimmunotherapy R-FND with Rituximab Consolidation Followed by Randomization Between Rituximab Maintenance Vs. Observation As First Line Treatment in Elderly Patients with Advanced Follicular Lymphoma (FL): Final Results of a Prospective Randomized Trial by Italian Lymphoma Foundation (FIL)

Abstract 777Introduction. Fludarabine containing regimens are effective in FL; the role of Rituximab (R) maintenance has been established recently. Aim of the study was to investigate efficacy and safety of R-maintenance vs. observation in elderly FL patients who respond to a brief chemo-immunotherapy with four courses of R-FND + four doses of Rituximab as consolidation. Methods. From January 2004 to December 2007, elderly patients (age 60–75) with untreated advanced stage FL who required treatment, were enrolled by 33 FIL centers. Treatment plan was: four courses of R-FND (standard doses of Rituximab, Fludarabine, Mitoxantrone, Dexamethasone) every 28 days followed by four weekly Rituximab infusions as consolidation; responding (Complete Response, CR + CRu + Partial Response, PR) patients were randomized between a short Rituximab maintenance with a single dose every two months for a total of four doses (Arm A) or observation (Arm B). Qualitative and quantitative PCR monitoring for IgH/Bcl-2 rearrangement on bone marrow (BM) was performed at diagnosis, after R-FND and R consolidation and during maintenance/observation. Results. 242 patients were enrolled at diagnosis in the study and 234 were eligible for treatment: median age was 66 yrs; advanced stage II 14%, stage III 21% and stage IV 65%; BM involvement and B symptoms were documented in 55% and 18% respectively. According to FLIPI risk patients were: Low 11%, Intermediate 34%, High 55%. According to Comprehensive Geriatric Assessment (CGA), concomitant illness were: one in 38% and greater than or equal to two in 23% of patients. Qualitative PCR analysis for IgH/Bcl-2, performed in 223 patients at diagnosis, was positive in 49%. Two hundred and two (86%) patients completed the induction treatment and were randomized between maintenance or observation; 32 were not because of stable/progressive disease (15), adverse events (nine) or other causes (eight). At the end of chemoimmunoterapy and consolidation overall response rate was 86% with 68% CR and 18% PR. After four courses of chemo-immunotherapy, 90 patients were in PR of whom 37 (41%) were converted to CR with the addition of Rituximab consolidation. As regard to Bcl2 analysis, PCR negativity was detected in 61% after R-FND and increased to 73% after R consolidation. With a median follow-up of 33 months, two-years Overall Survival and Progression Free Survival (PFS) were 93% (95% CI 92%–97%) and 77% (95% CI 71%–93%), respectively. Two-years PFS according to maintenance/observation phase was: 80% vs 68% (p.225), Figure 1. Two-years PFS rates according to FLIPI score were 87% for low/intermediate risk and 70% for high risk (p < 0.0001). A total of 1119 courses were delivered; the most frequent CTC grade 3–4 toxicity was neutropenia in 25% of the courses, with only 13 events of serious infections. Two toxic deaths during treatment (0.8%) occurred: 1 HBV reactivation and 1 Steven Johnson syndrome. In the maintenance/observation phase the following severe (WHO grade 3–4) toxicities were recorded: 15 patients experienced neutropenia, 8 cardiac events, 4 infections; no other relevant toxicities were recorded. Second malignancy were recorded in 11 patients. Conclusions. a short term chemo-immunotherapy R-FND + Rituximab consolidation is able to achieve high CR rate and a good two-years PFS in elderly FL patients. Good results were also observed in higk-risk FLIPI score. Two-years PFS of 80% in patients randomized to R maintenance was promising although there was no statistical difference compared to observation. This finding may be attributed to the relatively short follow-up or to the choice of a short course of Rituximab maintenance (only four doses) or both. [Display omitted] Disclosures:Vitolo:Jannsen-Cilag: Speakers Bureau; Celgene: Speakers Bureau; Roche Italy: Speakers Bureau. Off Label Use: The study includes use of Rituximab as maintenance in responding patients after first line chemoimmunotherapy. Gamba:Roche Italia: Employment. Supekar:Roche Italia: Employment.

The detection of minimal residual disease status in chronic lymphocytic leukemia

In this issue of Clinical Cytometry, Durrieu et al. on behalf of GEIL-GOELAMS present evidence that circulating levels of CD19+ CD5+ chronic lymphocytic leukemia (CLL)-like cells can be used to define a threshold for the detection of minimal residual disease (MRD) in CLL (this issue: page 346). This study was performed in 16 different hematology laboratories or services, and the data is analyzed centrally. The panel consisted of five tubes of four reagents each with CD19 and CD5 being present in each tube. They determined that the level of two CLL-like immunophenotypes CD19+/CD5+/CD43int/CD79blo and CD19+/ CD5+/CD81lo/CD22lo were less than 4 × 10−4 per WBC in unwashed, lyzed normal whole blood. Levels greater than this found in post treatment CLL samples were taken to signify the presence of MRD. The author further state that they are unable to determine monoclonality using light chain restriction due to their polyclonal nature in normal blood donors and the presence of cytophilic antibodies being present in the unwashed, lyzed method. And that bright CD5+ B cells are often lambda positive, and polyclonal. I have several preferences (biases) in this matter, and they include the use of CD20 rather than CD19 or preferably both CD20 and CD19 in combination to define B cells and the clone, demonstration of monoclonality or monotypia, and that reports be based on the absolute cell-count (WBC or absolute lymphocyte count ALC) and not just the percentage < or > 10−4. If the WBC is used, it should be used in conjunction with the ALC and even a B cell absolute count. I sympathize with the problem of cytophilic antibodies but in monoclonal B cell lymphocytosis studies, values of 5–50 light chain restricted B cells per microliter can be routinely detected (1). I was also surprised to see that the lower range of 1–3% CD5+ B cells seems to be the norm, whereas values of 10–25% seem to be more the rule. The European Research Initiative on CLL (ERIC) has published a standardized four-color approach to MRD detection in CLL (2). Both the authors of that study and this study find a WBC threshold of 10−4 below which is considered MRD negativity. The ERIC study allows for the primary role of kappa lambda tube for historical purposes but favors the combination of CD20/CD38/CD19/CD5 over the combinations of CD43/CD79b and CD81/CD22. They further point out the need for the evaluation of gate contamination, number of total events collected (500,000), and operator training. Certain precautions are required for differentiating between blood and marrow involvement in the setting of antibody therapies. However, due to the correlation of MRD between blood and marrow, blood should be the first site tested for MRD. The complete absence of B cells (B cell aplasia) might also be taken as a clinical measure of MRD. If ascertainment of marrow involvement in this setting were considered important, a bone marrow study would be indicated. Conversely, the timing of the blood MRD analysis could be postponed. The German CLL Study Group have also standardized three four tube panels of four-color reagents using a larger volume of blood, and where appropriate 2 million leucocytes were collected (3). This paper also shows that the overall ability of MRD flow is to detect and quantify residual CLL cells and is not affected by the addition of rituximab to FC chemotherapy (3). In a 2005 editorial, Montserrat (4) called for standardization and revision of 1996 NCI response guidelines to include MRD negative status as a goal. In 2008, Hallek et al. (5) revised the NCI guidelines to include not only a definition of MRD but also encouraged that the MRD detection become part of future CLL clinical trials because MRD negative status has prognostic impact. The GCLLSC, ERIC, and GEIL studies have all demonstrated that multicolor flow cytometry can meet the needs of a robust MRD assay. All three groups used a four-color, five tube panel and a sequential gating strategy. Newer clinical flow cytometers now allow for the use of 6–8 colors. The Salamanca group has developed an automated method for doing MRD detection by merging files on the same patient with the addition normal donor virtual 1:1 dilution as a control (6). Knowledge of the original CLL immunophenotype would be useful. One could envision an integration of the GCLLSC, ERIC, and GEIL methods combining CD19/CD20/CD5/CD38/CD79b/ CD22/CD41/CD81 and CD19/CD20/CD5/CD45/CD3/CD14/kappa/lambda. Del Poeta et al. (7) concluded that the addition of rituximab consolidation and maintenance therapy prolonged response duration significantly in patients with MRD + CLL. MRD detection is indicated in the investigation, care, and treatment of the CLL patient. Clinical trials will be required to answer the question of overall survival in CLL. Regardless, CLL remains a model disease for the appropriate treatment of the elderly with progressive disease.

Rituximab (R) Maintenance Versus Observation After Short Term Chemoimmunotherapy R-FND as First Line Treatment in Elderly Patients with Advanced Follicular Lymphoma (FL): Updated Results and Safety of the Maintenance of An Intergruppo Italiano Linfomi (IIL) Randomized Trial.

Abstract 1706Poster Board I-732 Introductionin order to maintain efficacy and reduce toxicity of the treatment in elderly follicular lymphoma (FL) patients, we designed a study with a short chemo-immunotherapy R-FND with Rituximab consolidation followed by randomization between R maintenance or observation. Material and methods: From January 2004 to December 2007, 242 patients (age 60-75) with untreated advanced stage FL were enrolled by 33 IIL centres. Treatment plan was: 4 courses of R-FND (standard doses of Rituximab, Fludarabine, Mitoxantrone, Dexamethasone) every 28 days followed by 4 weekly Rituximab infusions as consolidation; responding (CR+CRu+PR) patients were randomized between Rituximab maintenance, one dose every 2 months for a total of 4 doses or observation. Qualitative and quantitative PCR monitoring for IgH/Bcl-2 rearrangement on bone marrow (BM) was performed at diagnosis, after R-FND and R consolidation and during maintenance/observation. Results234 patients were eligible for the study: median age was 66 yrs; advanced stage II 14%, stage III 21% and stage IV 65%; BM involvement and B symptoms were documented in 55% and 18% respectively. FLIPI score was: Low 11%, Intermediate 34%, High 55%. One and 2 or more comorbidities were present in 36% and 23% of the patients respectively. Qualitative PCR analysis for IgH/Bcl-2 was performed in 223 patients at diagnosis and 51% were positive. Two hundred and two (86%) patients completed the induction treatment and were randomized between maintenance or observation; 32 were not because of: stable/progressive disease (16), adverse events (10) or other causes (6). Overall response at the end of treatment was 86% with 69% CR and 18% PR; PCR negativity at the end of treatment was 75%. Rituximab consolidation was able to induce CR in 37/90 (41%) partial responders and to increase PCR negativity from 61% to 75%. With a median follow-up of 22 months, two-years OS and PFS were 92% (95% CI 87%-95%) and 75% (95% CI 68%-81%), respectively (see Figure). [Display omitted] Two-years PFS rates according to FLIPI score were 85% for low/intermediate risk and 65% for high risk (p < 0.001); 2-years PFS rates were 57% and 79% respectively in patients with and without B symptoms (p < 0.001). The patients in more advanced decade (> 70 years) or those with 2 or more comorbidities did as well as younger ones or those with one or no comorbidities: 2-yr PFS rates for patients more or less seventy were 73% vs 76% (p = 0.39); for patients with ≥2 comorbidities or one or none were 84% vs 67% vs 76%, respectively (p = 0.82). A total of 1119 courses were delivered; the most frequent CTC grade 3-4 toxicity was neutropenia in 25% of the courses, with only 13 serious infections. One patients developed acute myelogenous leukaemia during treatment and died. Two toxic deaths during treatment (0.8%) occurred: 1 HBV reactivation and 1 Steven Johnson syndrome. So far 212 patients are alive; besides the above mentioned deaths, 15 patients died of lymphoma, 2 died of cardiac failure, 1 died of stroke and 1 died of drowning. So far too few events occurred to proper analyse the efficacy of the Rituximab maintenance. In the maintenance/observation phase the following severe (WHO grade 3-4) toxicities were recorded: 15 patients experienced neutropenia, seven cardiac events, four infections; no other relevant toxicities were recorded. The cumulative incidences of toxic events accounting for competing events at 18 months for maintenance arm (Arm A) versus observation arm (Arm B) were as follows: neutropenia 17% vs 1% (p<0.001); infections 2% vs 2% (p = 0.586); cardiac events 4% vs 4% (p= 0.627). Conclusionsa short term chemo-immunotherapy R-FND + Rituximab consolidation is safe and effective with a good 2-yr PFS rate also in patients with high risk FLIPI score or in patients in more advanced decade or with comorbidities. Rituximab maintenance is safe with a more frequent neutropenia that was not associated with an increased risk of infections. Final results of the study will provide insights on the role of Rituximab maintenance after R-chemotherapy. DisclosuresVitolo:Roche: Lecture fees; Mundipharma: Lecture fees. Off Label Use: Study was supported by Roche: Rituximab maintenance in first line treatment is off-label. Boccomini:Roche: Lecture fees. Ladetto:Roche Italy: Research Funding; Amgen: Honoraria, Research Funding.

Treatment with Fludarabine and Rituximab Produces Extended Overall Survival (OS) and Progression-Free Survival (PFS) in Chronic Lymphocytic Leukemia (CLL) without Increased Risk of Second Malignancy: Long-Term Follow up of CALGB Study 9712.

Abstract 539 Introduction:The addition of rituximab to fludarabine-based regimens in CLL has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, and development of secondary malignancies has been limited. Patients and Methods:We report the long-term follow up of the chemoimmunotherapy trial CALGB 9712 (Blood 2003;101:6-14). This trial randomized 104 untreated, symptomatic patients to receive either 6 monthly cycles of fludarabine plus rituximab (FR) followed 2 months later by 4 weekly doses of rituximab (concurrent arm) or 6 monthly cycles of single agent fludarabine followed by rituximab consolidation using 4 weekly doses (sequential arm). With a median follow up of 92 months (range: 60-107), we analyzed the updated CALGB database and flow sheets submitted by treating physicians. Results:The overall response rate (ORR) was 84% (95% CI: 77%-91%), with a 90% ORR in the concurrent group (95% CI: 82%-98%) and a 77% ORR in the sequential group (95% CI: 66%-89%). Complete response (CR) was seen in 38% of patients (95% CI: 30%-45%), and partial response (PR) in 46% (95% CI: 38%-54%). The median OS was 85 months (95% CI: 71-95), with 71% of patients alive at 5 years (95% CI: 61%-79%). The median PFS was 37 months (95% CI: 27-45), with 27% progression-free at 5 years (95% CI: 19%-36%). With long-term follow up, the estimated median OS and PFS for the concurrent group were 84 months (95% CI: 57-100) and 32 months (95% CI: 23-55), respectively; the median OS and PFS for the sequential group were 91 months (95% CI: 71-110) and 40 months (95% CI: 23-50), respectively. Patients with del(17p13.1)/del(11q22.3)(18 patients) and unmutated IgVH(43 patients) continue to have an inferior OS (P=0.01 and P=0.04, respectively) and PFS (P=0.03 and P=0.04, respectively) compared to those without these abnormalities. We next assessed the frequency of therapy-related myeloid neoplasms (t-MN) and other cancers occurring after this chemoimmunotherapy regimen. No patient has developed MDS or AML prior to relapse. One patient (1%) developed t-MDS following relapse and receipt of FCR 41 months after completing trial therapy; t-MDS was diagnosed 9 months later. Richter's transformation was noted in three (3%) of the CALGB 9712 patients with large cell (n=2) or Hodgkin lymphoma (n=1). Second malignancies have included localized basal cell or squamous cell skin cancer in 12 (12%) patients whereas 11 (11%) have developed other epithelial malignancies including 4 GI, 3 lung, 3 melanomas, and 1 prostate cancer. Conclusions:Long-term follow up of patients enrolled on CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab, given either concurrently or sequentially, with an estimated 17%(95% CI: 9%-27%) of responders still in remission 8 years later. Looking at other published data, patients treated with FR administered concurrently or sequentially do not appear to have an increased risk of t-MN or second cancers. These long-term data reaffirm that FR is one of several acceptable frontline treatments for symptomatic patients with CLL. Disclosures:Morrison:Genentech: Speakers Bureau.

Rituximab Maintenance Following Chemoimmunotherapy Improves Outcome in B-Cell Chronic Lymphocytic Leukemia.

Abstract 2364Poster Board II-341The treatment goal of B-cell chronic lymphocytic leukemia (B-CLL) has already shifted from symptom palliation to the attainment of maximal disease control combining purine analogs with monoclonal antibodies. This immunochemotherapeutic approach resulted both in more complete responses (CR) and longer response duration, often remaining only a minimal residual disease (MRD) detectable by flow cytometry. We treated in first line 120 B-CLL symptomatic patients (pts), median age 62 years, with six monthly courses of intravenous or oral fludarabine at conventional doses and then, after a median time of 31 days, with four weekly doses (375 mg/sqm) of rituximab (rtx). Fourteen pts had a low Rai stage, 103 an intermediate stage and 3 a high stage. We defined as high risk pts having at least two of these markers: unmutated IgVH, CD38>30%, ZAP-70>20%, intermediate unfavorable cytogenetics (trisomy 12 or del11q or del17p). Based on NCI criteria, 92/120 (77%) pts achieved a CR, 24/120 (20%) a partial remission (PR) and 4/120 (3%) no response or progression. Ten pts underwent grade 3 (WHO) infective lung toxicity, 1 patient acute fatal B hepatitis and 2 pts progressed towards Richter's syndrome. Hematologic toxicity included mainly neutropenia (grade 3 and/or 4 in 56 pts) and thrombocytopenia (grade 3 and/or 4 in 8 pts). Fifty-four pts either in CR with B-CLL bone marrow cells >1% (MRD+, n=16 pts) or in CR MRD negative, but with B-CLL peripheral cells going up >1000/microl within 1 year after induction (n=22 pts) or in PR (n=16 pts), underwent consolidation and maintenance therapy with four monthly cycles of rtx at 375 mg/sqm followed by twelve monthly low doses of rtx (150 mg/sqm). The median follow-up duration was 50 months. All treated pts experienced a long progression-free survival from the end of induction treatment (40% at 9 years). On the other hand, global overall survival (OS) was 54% at 10 years. Nevertheless, CLL pts undergoing consolidation and maintenance therapy (n=54) showed a longer response duration vs MRD+ not consolidated pts (n=16; 75% vs 9% at 4 years; P<0.00001, Figure). Noteworthy, persistently MRD negative (>1 year) pts (n=43) showed a very long response duration (79% at 6 years, Figure). Moreover, OS was shorter in MRD+ not consolidated pts (0% vs 79% at 15 years; P=0.0007). Noteworthy, within the high risk subset (n=48), consolidated pts (n=17) showed a longer response duration (56% vs 0% at 2.5 years, P=0.003) vs MRD+ not consolidated pts (n=11). Therefore, rituximab consolidation and maintenance immunotherapy improve response duration in B-CLL, thus potentially increasing OS, also within the high risk subset. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Use of alemtuzumab and rituximab consolidation in CLL: Pros and cons

As new therapeutic approaches have improved responses and outcomes in the treatment of chronic lymphocytic leukemia (CLL), the scientific community focuses now on diagnostic procedures and definitions of response in CLL. The use of monoclonal antibodies in particular has made it possible to treat CLL more effectively. The success of these new therapeutic tools can be traced back to the eradication of detectable disease in a significant number of patients. Therefore, the evaluation of minimal residual disease has become an important end point within clinical trials. This article describes various methods of assessing minimal residual disease and presents data demonstrating that new therapeutic approaches can eliminate residual malignant cells at the highest levels of sensitivity currently available. Although initial evidence suggests that the use of alemtuzumab induces a survival benefit when used in the consolidation setting, important safety issues remain to be resolved before this approach can be introduced in routine practice.

Phase II study of low-grade non-Hodgkin lymphomas with fludarabine and mitoxantrone followed by rituximab consolidation: Promising results in marginal zone lymphoma

The majority of patients with indolent lymphomas relapse due to minimal residual disease (MRD). In the present study, we sought to determine whether by using rituximab consolidation, for eradication of MRD, following induction chemotherapy with fludarabine and mitoxantrone (FN) combination could improve the outcome of indolent lymphomas. Patients with indolent lymphoma received fludarabine 25 mg/m2 Day 1 – 3 and mitoxantrone 10 mg/m2 on Day 1 every 28 days. Patients who attained a response (complete response, CR or partial response, PR) received four weekly doses of Rituximab 375 mg/m2 1 month and 3 months after completion of treatment. Forty-five patients were entered into this Phase II trial. The median follow-up time was 39 months. The median number of delivered cycles was 6. Fifty-three percent of patients attained a CR and 38% a PR for an overall response rate of 91%. One patient had stable disease, one had progression of the disease, whereas 2 were non-evaluable. After a median follow-up of 39 months, 32 of 46 patients (74%) are alive and disease-free. Grade III and IV toxicities included leucopenia (37%), neutropenia (28%), thrombocytopenia (7%), anemia (4%), and diarrhea (2%). Grade V toxicities included septic death in one patient and death due to hepatititis B reactivation 6 months after the last Rituximab dose in another patient. FN followed by R consolidation is a well-tolerated and active regimen in the treatment of patients with indolent lymphomas. Further follow-up is required to determine if these remissions are maintained.

CEOP-21 Versus CEOP-14 Chemotherapy With or Without Rituximab for the First-Line Treatment of Patients With Aggressive Lymphomas: Results of the HE22A99 Trial of the Hellenic Cooperative Oncology Group

In this study we investigated whether administering CEOP (cyclophosphamide, epirubicin, vincristine [Oncovin], and prednisone) every 2 weeks (CEOP-14) instead of every 3 weeks (the standard CEOP-21 regimen) improves outcomes in patients with previously untreated aggressive lymphomas. In a secondary analysis we evaluated the impact of adding rituximab to CEOP-14/CEOP-21 chemotherapy. The trial opened in March 1999, and patients were randomly assigned to either CEOP-14 or CEOP-21. All patients enrolled from May 2002 onward received rituximab with each chemotherapy cycle, and those attaining a complete response received rituximab consolidation. Complete and overall response rates in the CEOP-21 +/- rituximab (N = 114) and CEOP-14 +/- rituximab (N = 103) arms were similar, as were the overall survival (P = 0.769) and time to progression distributions (P = 0.969). Rituximab was shown to have a beneficial effect both on the overall survival and on the time to progression. Thus far, no significant improvement in outcome has been demonstrated with CEOP-14 +/- rituximab versus CEOP-21 +/- rituximab. However, with addition of rituximab to CEOP-21/CEOP-14, significant improvements in time to progression and overall survival were achieved.

CHOP chemotherapy followed by Rituximab consolidation as first line treatment in patients with follicular lymphoma. Long‐term follow‐up of a phase 2 trial

CHOP chemotherapy followed by Rituximab consolidation as first line treatment in patients with follicular lymphoma. Long‐term follow‐up of a phase 2 trial

Long Term Remission in Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL) with Rituximab Consolidation after High-Dose Chemotherapy and Autologous Stem Cell Transplantation: Extended Follow-Up of a Multicenter Phase II Study.

We investigated the efficacy of rituximab given after high-dose therapy (HDT) and autologous peripheral blood stem cell transplantation (ASCT) in order to prevent relapse by clearance of minimal residual disease in patients with advanced FL and MCL. Eligibility included newly diagnosed stage III/IV t(14;18)+ FL or newly diagnosed or relapsed patients with stage III/IV t(11;14)+ MCL. 35% of patients had elevated LDH levels, 23% had B-symptoms. The age-adjusted IPI risk category was low-intermediate in 65% and high-intermediate in 35% of the patients. Initial cytoreduction consisted of VACOP-B (6 weeks) or CHOP chemotherapy, followed by G-CSF supported VIP-(E) or DexaBEAM therapy. PBSC were harvested, and positive selection of CD34+ cells was performed. HDT consisted of TBI (6x2 Gy) and cyclophosphamide (120 mg/kg), followed by CD34+ PBSCT (7.16x106 CD34+/kg; range 2.4–22.7). A median of 62 days (range 38–108) after transplantation, rituximab was given at a dose of 375 mg/m2 weekly for 4 weeks. No additional treatment was given thereafter. Between October 1997 and July 2001, 31 patients were included. Median age at transplantation was 49 (31–60) years. One patient died early after HDT due to neutropenic septicemia before rituximab administration. Therefore, only 30 patients were evaluable for safety and efficacy of rituximab after HDT and ASCT (FL n=20, MCL n=10). Twenty seven were evaluable for MRD. In the intent-to-treat (ITT) analysis, 7 treatment failures were observed: two FL patients relapsed at 25 and 33 months post transplant, four MCL patients relapsed at 24, 38, 47 and 48 months post transplant, and one MCL patient died unexpectedly in complete remission (CR) at 19 months post transplant. One of the MCL patients died at 37 months post transplant due to progressive disease. Currently, 28 of 30 patients are alive. With an extended median follow up of 61 months (18.7 – 87.5 months) after ASCT, the progression-free survival (PFS) for the ITT population is 76.7%, the median PFS has not yet been reached. In the FL population, the PFS at 5 years is 90% (95% CI: 65.6 – 97.4) whereas in the MCL population, the PFS is 46.2% (95% CI: 14.7 – 73.3) (log rank p=0.0168). The overall survival (OS) at 5 years for the ITT population is 93.3% (95% CI; 75.6 – 98.3) with 100% OS in the FL patients and 79.4% (95% CI: 39.6 – 94.4) (log rank p=0.0400) in MCL patients. In summary, at an extended follow-up of 5 years, we show that one 4-week course of Rituximab consolidation after HDT and ASCT induces prolonged remissions in both FL and MCL. Futher improvement in MCL therapy is warranted.

High Dose Therapy / ASCT with Rituximab for In-Vivo Purging and Post-ASCT Consolidation in Relapsed Follicular Lymphoma Achieves Prolonged Clinical and Molecular Remissions.

High-dose therapy and autologous stem cell transplantation (HDT/ASCT) is associated with prolonged remissions in relapsed follicular lymphoma (FL). Molecular remission in the graft and post ASCT predicts durable remissions and is a desirable endpoint. Rituximab (R) as an in vivo purge prior to HDT/ASCT and as consolidation after ASCT may help achieve this. To study this question, patients with relapsed FL were enrolled in a prospective, non-comparative phase II study between January 1998 and April 2000.Methods: 23 consecutive patients age <65 yrs with <3 relapses underwent HDT/ASCT with CBV (Cyclophosphamide, BCNU and VP-16) following salvage with CHOP or DHAP. Patients achieving ≥75% reduction in bulk and <15% marrow involvement underwent stem cell mobilization with chemotherapy plus G-CSF 10 μg/kg daily x 5. R 375 mg/m2 was given as a single-dose purge prior to collection, and repeated as 4 weekly courses at 2 and 6 months post-ASCT. Samples for PCR detection of minimal residual disease (MRD) were taken from stem cell grafts, as well as blood and marrow for all patients with detectable disease at baseline. Response assessments were clinical, laboratory and radiologic, and analysis was intention-to-treat.Results: Median cohort age at assessment was 50 yrs (32–57). Median number of prior regimens was 3 (1–7) and total treatment cycles was 9 (3–28). Median response duration to the preceding regimen was 10 months (1–86). Transplants were a median 2.4 years after diagnosis. At median follow-up of 4.5 yrs (1.3–6.3), there have been 10 relapses at a median of 2.8 yrs. 3 patients have died, 2 with relapse and one of presumptive sudden cardiac death. Significant toxicities were seen: 11 episodes of pneumonia (1 fungal), 4 episodes of herpes zoster (1 grade 3), 4 early episodes of grade 3/4 interstitial pneumonitis, and 1 episode each of grade 4 TTP and grade 3 optic neuritis. One patient developed AML at 4.7 years post-ASCT. Immune recovery has been delayed; at 600 days post ASCT, 16/18 (89%) of evaluable patients had not recovered IgG levels to normal. At baseline, 12/23 patients had detectable markers by PCR analysis (sensitivity 0.01%) for t(14;18) or patient-specific VDJ rearrangements in marrow or blood. Of these, all achieved at least a brief molecular remission in blood and marrow, 11/12 doing so pre-R consolidation. 5/12 patients have since relapsed at a median 3 yrs (2–4.5) post ASCT. Molecular relapse preceded clinical in 3/5 cases. 6/12 have had prolonged (median 4.8 yrs, range 3–5) molecular and clinical remissions. Median event-free survival for all patients is 63 months, with median overall survival not reached.Conclusions: HDT/ASCT with R for in vivo purging and post-ASCT consolidation for relapsed FL is feasible and associated with prolonged clinical and molecular remission. Delay in recovery of humoral immunity may play a role in the high incidence of infectious complications. A single infusion of Rituximab for in-vivo purging did not eradicate PCR detectable disease in the graft, although sustained molecular remissions of at least 24 months were achieved in 75% of evaluable patients post transplant, possibly due to post ASCT Rituximab consolidation. Whether this translates into survival benefit will require longer follow-up and further comparative studies.

Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study

Patients with follicular (FL) or mantle cell lymphoma (MCL) are incurable with conventional therapy. We investigated the safety and efficacy of rituximab consolidation after autologous stem cell transplantation (ASCT) in order to prevent relapse by clearance of minimal residual disease (MRD). Rituximab was given approximately 8 weeks after CD34+ cell enriched ASCT at 375 mg/m2, weekly for 4 weeks. Monitoring of MRD was performed by repetitive PCR analyses. Thirty-one patients were included; one died early after ASCT before rituximab administration. Thirty patients (20 FL, 10 MCL) were evaluable after rituximab consolidation, and 27 of these were assessable for MRD detection. Rituximab consolidation post-ASCT was safe, the most common toxicity being infection. At a median follow-up of 42 months (range 13-96) after ASCT, 25 patients were censored with an actuarial event-free survival (EFS) of 81% at 4 and 5 years. Four patients (two FL, two MCL) relapsed, and one additional MCL patient died unexpectedly in complete remission. PCR-negativity was observed in 22% of the patients before ASCT, 53% post-ASCT (P=0.0547), 72% after rituximab (P=0.0018) and 100% at 6 months post-transplant (P < 0.001). One single course of rituximab consolidation given after ASCT is safe, may help to eliminate MRD and may translate into improved EFS in both FL and MCL patients.

Clearing Minimal Residual Disease with Rituximab Consolidation Therapy

Advanced follicular and mantle cell lymphoma are currently incurable using conventional chemotherapy. As such, new and potentially more effective therapeutic approaches such as high-dose chemotherapy with autologous stem cell transplantation (ASCT) and consolidation using various types of therapy are being increasingly considered. Rituximab has been assessed as an in vivo purge and as consolidation therapy both first-line and in relapsed patients with follicular and mantle cell lymphoma. Data from a number of studies are reviewed, focusing on our recently reported phase II study of patients with follicular or mantle cell lymphoma who received one standard course of rituximab consolidation therapy after ASCT to show that using rituximab in the context of high-dose chemotherapy and ASCT may improve patient outcomes without compromising tolerability. Specifically, purging and consolidation using rituximab can improve clinical and molecular response rates, may eliminate minimal residual disease, and may improve survival. These studies suggest that rituximab may have an important role in improving the outcome of ASCT in patients with follicular or mantle cell lymphoma.