Results of a Prospective Randomized Trial of the German Low-Grade Lymphoma Study Group

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1 1014 Combined Cyclophosphamide, Vincristine, Doxorubicin, and Prednisone (CHOP) Improves Response Rates but Not Survival and Has Lower Hematologic Toxicity Compared With Combined Mitoxantrone, Chlorambucil, and Prednisone (MCP) in Follicular and Mantle Cell Lymphomas Results of a Prospective Randomized Trial of the German Low-Grade Lymphoma Study Group Christina Nickenig, MD 1 Martin Dreyling, MD 1 Eva Hoster, MD 1,2 Michael Pfreundschuh, MD 3 Lorenz Trumper, MD 4 Marcel Reiser, MD 5 Hannes Wandt, MD 6 Eva Lengfelder, MD 7 Michael Unterhalt, MD 1 Wolfgang Hiddemann, MD, PhD 1 and the German Low-Grade Lymphoma Study Group 1 Department of Internal Medicine III, Ludwig- Maximilians University, Munich Grosshadern, Germany. 2 Department of Medical Informatics, Biometrics, and Epidemiology, Ludwig-Maximilians University, Munich Grosshadern, Germany. 3 Department of Internal Medicine I, University of Hamburg, Hamburg, Germany. 4 Department of Hematology and Oncology, Georg August University, Gottingen, Germany. 5 Department of Internal Medicine I, University of Cologne, Cologne, Germany. 6 Department of Internal Medicine V, Hospital Nurnberg-Nord, Nurnberg, Germany. BACKGROUND. In patients with advanced-stage follicular lymphoma (FL) and mantle cell lymphoma (MCL), conventional chemotherapy remains a noncurative approach, and no major improvement in overall survival has been achieved in recent decades. METHODS. The German Low-Grade Lymphoma Study Group performed a randomized trial comparing combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) chemotherapy with combined mitoxantrone, chlorambucil, and prednisone (MCP) chemotherapy as first-line therapy for patients with advanced-stage FL or MCL. RESULTS. Three hundred sixty-three patients with advanced-stage FL (n ¼ 277 patients) or MCL (n ¼ 86 patients) entered the trial and were evaluable fully. CHOP resulted in a significantly higher overall response rate in patients with FL (91% vs. 82%; P ¼.026) and a similar tendency in patients with MCL (87% vs. 73%; P ¼.080). However, no significant differences were observed in the time to treatment failure or in overall survival. CHOP produced significantly more nonhematologic toxicities, whereas MCP was associated with more severe hematologic side effects. The proportion of patients who successfully underwent peripheral blood stem cell collection was significantly lower after MCP (44% vs. 93% after CHOP; P ¼.0003). CONCLUSIONS. Taking into account that, currently, chemotherapy regularly is combined with rituximab as first-line therapy for FL and MCL, the data from this study may have an impact on the type of chemotherapy to be applied in such combinations. Particularly in younger, high-risk patients who are candidates for autologous stem cell transplantation, CHOP should be preferred over MCP. Cancer 2006;107: Ó 2006 American Cancer Society. KEYWORDS: indolent lymphoma, chemotherapy, randomized trial, first-line therapy. 7 Department of Internal Medicine III, University of Mannheim, Mannheim, Germany. The authors dedicate this paper to Reza Parwaresch, who served as a reference pathologist for the German Low-Grade Lymphoma Study Group (GLSG) over many years and who died unexpectedly in November Address for reprints: Wolfgang Hiddemann, MD, PhD, Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, Munich, Germany; Fax: (011) ; wolfgang. hiddemann@med.uni-muenchen.de Received March 6, 2006; revision received April 27, 2006; accepted May 9, ª 2006 American Cancer Society DOI /cncr Published online 28 July 2006 in Wiley InterScience (

2 CHOP versus MCP in FL and MCL/Nickenig et al Follicular lymphoma (FL) and mantle cell lymphoma (MCL) represent major challenges to clinical research, because few improvements in outcome have been achieved over the last few decades. Recently, several new treatment approaches have been established that may result in a substantial improvement in the long-term outcome of patients with FL and MCL. One of these approaches is myeloablative radiochemotherapy with subsequent autologous stem cell transplantation (ASCT) as consolidation therapy in first remission. Results from 3 prospective, randomized studies indicate prolonged progression-free survival and, in 1 study, longer overall survival (OS). 1 3 The other major new approach includes use of the anti-cd20 antibody rituximab. This agent is highly effective in patients with recurrent and previously untreated, indolent lymphomas both as a single agent and in combination with chemotherapy. 4 7 Currently, 5 major studies have been completed that investigated different chemotherapeutic combinations with or without rituximab. All 5 trials consistently demonstrated significant improvements in remission rates, time to treatment failure (TTF), and response duration (RD) In 3 studies, OS also was prolonged by using the rituximab-chemotherapy (R-chemo) combination. Despite the consistent finding of a superior outcome after R-chemo combinations over chemotherapy alone, response rates and TTF or event-free survival (EFS) varied substantially between the different studies. This may be explained in part by the differences in patient profiles and also by differences in the efficacy of chemotherapeutic regimens. When analyzing the 4 trials that studied first-line therapy in more detail, rituximab combined with cyclophosphamide, vincristine, and prednisone (R-CVP) resulted in an overall response (OR) rate of 81% and a median TTF of 27 months. In contrast, R-CHOP and R-MCP revealed OR rates of 96% and 92%, respectively; and, in both studies, the median TTF has not been reached and will extend beyond 36 months. The data from rituximab combined with cyclophosphamide, and prednisone (CHVP) plus interferon (IFN; doxorubicin, vindesine, CHVP þ IFN) produced responses in between. Although 3 of the regimens described above (CVP, CHOP and CHVP þ IFN) are known well and are used broadly, the MCP combination is less common. It was derived from the combination of prednimustine and mitoxantrone (PmM), which was introduced by Landys in 1988, who reported a high remission rate in patients with recurrent and untreated, indolent lymphomas. 13 A subsequent trial by the German Low- Grade Lymphoma Study Group (GLSG) confirmed those data and also showed significantly greater antilymphoma activity and a more favorable toxicity profile for PmM when it was compared randomly with cyclophosphamide, vincristine, and prednisone (COP). 14 When prednimustine, which is an ester of chlorambucil and prednisone, was taken off of the market because of a high rate of secondary acute myeloid leukemias and myelodysplastic syndromes, chlorambucil andprednisonewereusedasseparateagents.hence, PmM was renamed MCP (mitoxantrone, chlorambucil, and prednisone). Based on the superiority of PmM versus COP, in the current study, we investigated whether PmM data could be improved. Therefore, in 1996, the GLSG embarked in a prospective, randomized comparison of MCP versus CHOP under the assumption that CHOP may increase the complete remission rate. MATERIALS AND METHODS Eligibility Criteria Patients age 18 years with previously untreated, advanced Stage III or IV FL, MCL, and lymphoplasmacytic lymphoma (LPL) according to the World Health Organization (WHO) classification 15 entered the trial between May 1996 and December The histologic diagnosis had to be confirmed by central pathology review. Patients with FL or LPL had to be in need of therapy as defined by 1) the presence of B-symptoms and/or 2) hematopoietic insufficiency, and/or 3) rapid progress of disease, and/or 4) bulky disease. Randomization and Treatment Protocols Eligible patients underwent a central randomization procedure for MCP versus CHOP with stratification for histology (FL, MCL, or LPL), age (age <60 years vs. age 60 years), and the number of risk factors according to the International Prognostic Index (2 vs. 3 except for age). The MCP regimen consisted of mitoxantrone at a dose of 8 mg/m 2 given intravenously on Days 1 and 2, chlorambucil at a dose of 3 3 mg/m 2 given orally on Days 1 through 5, and prednisone at a dose of 25 mg/m 2 given orally on Days 1 through 5 and was repeated every 4 weeks. The CHOP regimen consisted of intravenous applications of cyclophosphamide at a dose of 750 mg/m 2, vincristine at a dose of 1.4 mg/m 2 (maximum, 2 mg), doxorubicin at a dose of 50 mg/m 2 (all on Day 1), and oral prednisone at a dose of 100 mg/m 2 on Days 1 through 5 and was repeated every 3 weeks. Both regimens were applied for a total of 6 to 8 cycles. The number of cycles was determined by the quality of response to the first 4 treatment courses. Patients who achieved complete remission (CR) after 4 cycles received 6 courses. Patients who had a partial response (PR) after 4 cycles received 8 courses.

3 1016 CANCER September 1, 2006 / Volume 107 / Number 5 After 2 cycles, patients age <60 years were offered a second randomization for treatment in remission. It comprised in 1-arm intensification of dexamethasone at a dose of 3 8 mg given orally on Days 1 through 10, carmustine at a dose of 60 mg/m 2 per day on Day 2, melphalan at a dose of 20 mg/m 2 per day given intravenously on Day 3, etoposide at a dose of 75 mg/ m 2 per day given intravenously on Days 4 through 7, and cytosine arabinoside at a dose of mg/m 2 every 12 hours given intravenously on Days 4 through 7 (DexaBEAM) with subsequent stem cell harvest. If at least CD34-positive stem cells per kg bodyweight could be collected, then patients underwent myeloablative radiochemotherapy with total body irradiation (12 grays), cyclophosphamide at a dose of 60 mg/kg per day for 2 days, and stem cell retransfusion. The other arm consisted of IFN-a maintenance, which was initiated at a dose of 3 5million units per week. 16 The second randomization was stratified for histology, type of initial therapy (CHOP or MCP), and response after 2 cycles of treatment (CR, PR, or no remission). Patients age 60 years and patients who were not eligible for stem cell transplantation uniformly received IFN-a maintenance. Response Criteria and Evaluation Response to induction therapy was assessed after every 2 courses. Response evaluation included a physical examination, a complete blood count, serum biochemistry profile, chest X-ray, abdominal ultrasound, and computed tomography (CT) scans of the neck, chest, and abdomen. For follow-up, the same analyses were performed every 3 months, except that CT scans were repeated every 6 months. Response was defined according to the International Working Group criteria: A CR was defined as the disappearance of all lymphoma manifestations, includingthebonemarrow,foraminimumof4weeksand the normalization of peripheral blood counts. A PR was defined as the reduction of disease manifestations by 50% for >4 weeks. In a modification of the aforementioned criteria, the category of unconfirmed CR (CRu) was not used. Instead, patients who fulfilled the CR criteria but did not have a bone marrow biopsy with evaluable negative results were categorized with a PR. A minimal response (MR) was defined as a reduction <50% in all evaluable manifestations of lymphoma. Stable disease (SD) meant no significant reduction of evaluable lymphoma manifestations. Progressive disease (PD) consisted in the appearance of new lymphoma manifestations, an increase of more than 25% in the volume of measurable lymphomas or the recurrence of lymphoma-associated symptoms. The TTF was defined as the interval from trial recruitment to either failure of induction therapy (MR, SD, or PD), recurrence (after CR or PR), or death from any cause. RD was counted as the time between the end of successful induction therapy and progression of lymphoma or death from any cause. OS was calculated as the time from recruitment to the last followup or death from any cause. Treatment-related toxicity was evaluated according to the WHO criteria. 17 Trial Design and Statistical Analysis The primary trial endpoint was the CR rate, which was monitored continuously and was analyzed by means of a sequential procedure with planned interim analyses to allow a termination of randomization as soon as a significant difference between the 2 study arms was observed. Based on a 1-sided significance level of a ¼.05, the triangular test for the exact Fisher test was designed to detect an improvement of the CR rate from 35% observed with PmM to 60% after CHOP with a power of 95%. 18 Secondary analyses of response rates were performed by applying a 1-sided Fisher exact test. Secondary time-to-event parameters were analyzed with Kaplan Meier estimates and the log-rank test. Toxicity was compared by using a 2-sided Fisher exact test. Statistical analyses were done with the PEST (version 3; Reading University, Great Britain) and SAS (version 8.02; SAS Institute Inc.) software packages. Trial Conduct The current trial was carried out in accordance with the Helsinki Declaration. All patients gave their written informed consent after they were informed about the purpose and investigational nature of the trial. Prior to initiation, the trial received approval by the responsible ethics committees. It also was approved by the institutional review boards. RESULTS Patient Characteristics Five hundred six patients entered the trial between May 1996 and December 1998 and were randomized to receive either MCP or CHOP. Forty-two patients (8%) were excluded because of nonstudy histology, as revealed by the central pathologic review, and 4 patients were excluded because they had early-stage disease. Seventeen eligible patients in the CHOP arm and 28 eligible patients in the MCP arm were excluded because they did not receive the assigned therapy (5 patients and 9 patients, respectively), or because they did not complete therapy (9 patients and 18 patients, respectively), or for other reasons (3

4 CHOP versus MCP in FL and MCL/Nickenig et al TABLE 1 Patient Characteristics No. of patients (%) All FL MCL Characteristic CHOP MCP CHOP MCP CHOP MCP No. of evaluable patients Median age (range), y 56 (27 79) 55 (18 77) 55 (27 77) 53 (19 74) 61 (36 79) 62 (35 77) Male gender 128 (59) 114 (58) 66 (46) 72 (53) 40 (87) 31 (78) Stage IV disease 157 (72) 151 (76) 92 (65) 94 (70) 37 (80) 34 (85) Elevated serum LDH (n ¼ 387) 69 (34) 62 (34) 48 (36) 42 (34) 16 (36) 9 (25) ECOG 2(n ¼ 408) 24 (11) 24 (12) 16 (11) 16 (12) 3 (7) 6 (15) B-symptoms (n ¼ 413) 91 (42) 89 (45) 59 (42) 61 (46) 22 (48) 15 (38) IPI (n ¼ 378) Low risk 70 (35) 70 (35) 51 (39) 41 (34) 12 (28) 8 (22) Low-intermediate risk 78 (39) 78 (39) 49 (37) 51 (42) 16 (37) 13 (36) High-intermediate risk 36 (18) 36 (18) 23 (17) 23 (19) 9 (21) 12 (33) High risk 16 (8) 16 (8) 9 (7) 6 (5) 6 (14) 3 (8) FL indicates follicular lymphoma; MCL, mantle cell lymphoma; CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone; LDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index. patients and 1 patient, respectively). In total, 415 patients were evaluable according to the protocol, including 217 patients in the CHOP arm and 198 patients in the MCP arm. Overall, 277 evaluable patients had FL (67%), 86 evaluable patients had MCL (21%), and 52 evaluable patients had LPL (13%). Patient characteristics were comparable between the treatment groups for entire cohort and among patients with FL and MCL (Table 1). Response to Therapy The primary trial hypothesis was not confirmed; in the CHOP arm, 40 of 217 randomized patients achieved a CR (18%) compared with 27 of 198 patients (14%) in the MCP arm (P ¼.066). However, the OR rate was significantly higher after CHOP than after MCP, with 187 of 217 evaluable patients (86%) achieving a CR or PR versus only 152 of 198 evaluable patients (77%) in the MCP arm (P ¼.0094). Similar results were obtained in the intent-totreat analysis of 446 patients eligible with respect to histology and stage. Forty of 228 patients who were randomized to receive CHOP achieved a CR (18%), and 194 patients achieved a PR or CR (85%). In contrast, 28 of 218 patients who were randomized to receive MCP achieved a CR after induction therapy (13%; P ¼.11) and 169 patients responded with a PR or CR (78%; P ¼.027). Similar results were obtained when patients with FL and MCL were analyzed separately. From the 277 TABLE 2 Treatment Results from Combined Cyclophosphamide, Vincristine, Doxorubicin, and Prednisone versus Combined Mitoxantrone, Chlorambucil, and Prednisone: Response Rates, Response Duration, Time to Treatment Failure, and Overall Survival in Patients with Follicular Lymphoma Variable CHOP (n = 142) RR (95% CI), % MCP (n = 135) Response CR þ PR.026 No. of patients Rate 91 (85 95) 82 (75 88) CR.064 No. of patients Rate 22 (15 30) 14 (9 21) RD (n ¼ 240).16 Median, mo y 58 (50 67) 64 (55 73) 5 y 36 (28 45) 45 (35 56) TTF.70 Median, mo y 54 (46 62) 56 (48 65) 5 y 33 (25 41) 39 (30 48) OS.29 Median, mo NR NR 2 y 89 (84 94) 86 (80 92) 5 y 74 (67 82) 69 (61 77) Significance (P) RR indicates response rate; 95% CI, 95% confidence interval; CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone; CR, complete response; PR, partial response; RD, response duration; TTF, time to treatment failure; OS, overall survival; NR, not reached.

5 1018 CANCER September 1, 2006 / Volume 107 / Number 5 TABLE 3 Treatment Results from Combined Cyclophosphamide, Vincristine, Doxorubicin, and Prednisone versus Combined Mitoxantrone, Chlorambucil, and Prednisone: Response Rates, Response Duration, Time to Treatment Failure, and Overall Survival in Patients with Mantle Cell Lymphoma RR (95% CI) Variable CHOP (n = 46) MCP (n = 40) Significance (P) Response CR þ PR.080 No. of patients Rate 87 (74 95) 73 (56 85) CR.81 No. of patients 7 8 Rate 15 (6 29) 20 (9 36) RD (n ¼ 69) Median, mo y 45 (30 60) 41 (23 59) 5 y 23 (10 37) 13 (0 26) TTF Median, mo y 46 (31 60) 30 (16 44) 5 y 20 (8 32) 9 (0 19) OS Median, mo y 85 (74 95) 82 (70 94) 5 y 57 (43 72) 31 (15 47) RR indicates response rate; 95% CI, 95% confidence interval; CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone; CR, complete response; PR, partial response; RD, response duration; TTF, time to treatment failure; OS, overall survival. patients with FL, 142 patients were randomized to receive CHOP, and 135 patients were randomized to receive MCP. The OR rate (CRs and PRs) was significantly higher after CHOP (91% vs. 82% after MCP; P ¼.026), whereas no significant differences were observed in CR rates (22% vs. 14%;, respectively; P ¼.064) (Table 2). A similar tendency to a higher OR rate also was observed in the 86 patients with MCL, who had an overall (CR þ PR) response rate of 87% after CHOP compared with 73% after MCP (P ¼.08). The CR rates were 15% after CHOP and 20% after MCP (P ¼.8) (Table 3). FIGURE 1. Time to treatment failure in patients with follicular lymphoma. CHOP indicates cyclophosphamide, vincristine, doxorubicin, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone. median RD was 34 months, the 2-year RD was 58%, and the 5-year RD was 39% (P ¼.35). Among the patients with FL, 78 recurrences or deaths (60%) occurred after CHOP, and the median RD was 29 months. In the MCP arm, 57 recurrences or deaths (51%) occurred, and the median RD was 51 months (P ¼.16). Among the patients with MCL, 31 recurrences or deaths (78%) occurred after CHOP, and the a median RD was 21 months. In the MCP arm, 25 recurrences or deaths (86%) occurred, and the median RD was 15 months (P ¼.4). Among 339 patients who achieved at least a PR, 91 patients went on to receive high-dose consolidation with subsequent ASCT, and 229 patients started IFN-a maintenance as postremission therapy. In 19 patients, no postremission therapy was documented. Because the results indicated that RD was significantly superior after ASCT, the comparison of RD after CHOP versus MCP was done separately for the 2 postremission therapy groups. In both groups, no differences in RD between CHOP and MCP were observed, and there were no differences observed when patients with FL and patients with MCL were analyzed separately (data not shown). Response Duration One hundred twenty recurrences or deaths (64%) among 187 responders were observed in the CHOP arm after a median follow-up of 57 months. The median RD in patients who achieved a CR or PR was 27 months, with a 2-year-RD of 55% and a 5-year RD of 33%. Similarly, 89 recurrences or deaths (59%) among 152 responders were observed in the MCP arm. The TTF In 150 of 217 patients (69%) who received CHOP, recurrences, deaths, or failures of induction therapy were observed after a median follow-up of 61 months. The median TTF was 25 months. The corresponding data for patients who received MCP were treatment failures in 135 of 198 patients (68%) and a median TTF of 21 months (P ¼.74).

6 CHOP versus MCP in FL and MCL/Nickenig et al FIGURE 2. Time to treatment failure in patients with mantle cell lymphoma. CHOP indicates cyclophosphamide, vincristine, doxorubicin, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone. FIGURE 4. Overall survival in patients with mantle cell lymphoma. CHOP indicates cyclophosphamide, vincristine, doxorubicin, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone. year and 5-year survival rates were 87% and 68%, respectively. Seventy-three of 198 patients (37%) in the MCP arm died, and their 2-year and 5-year survival rates were 84% and 61%, respectively (P ¼.14). The 2-year and 5-year OS rates in patients with FL who received CHOP were 89% and 74%, respectively; whereas, in the MCP arm, the 2-year and 5-year OS rates were 86% and 69%, respectively (P ¼.29) (Fig. 3). The median OS in patients with MCL was 61 months after CHOP compared with 48 months after MCP (P ¼.058) (Fig. 4). FIGURE 3. Overall survival in patients with follicular lymphoma. CHOP indicates cyclophosphamide, vincristine, doxorubicin, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone. Similar results emerged for the separate evaluation of patients with FL and patients with MCL. Ninety-one events were observed among 142 patients with FL who received CHOP (median TTF, 30 months), and 81 of 135 patients showed treatment failure in the MCP arm (median TTF, 32 months; P ¼.7) (Fig. 1). In the patients with MCL, treatment failures were observed in 37 of 46 patients (80%) in the CHOP arm with a median TTF of 21 months, whereas treatment failures were observed in 36 of 40 patients (93%) in the MCP arm (median TTF, 15 months; P ¼.14) (Fig. 2). OS After a median follow-up of 61 months, 67 of 217 patients (31%) in the CHOP arm died, and their 2- Side Effects Treatment-associated side effects encompassed predominantly myelosuppression (Table 4). Serious granulocytopenia was observed more frequently after MCP (58%) than after CHOP (42%; P ¼.0041). However, the frequency of infectious complications was similar in both study arms (3% in both arms; P ¼.37). Thrombocytopenia also was observed more frequently after MCP (35% vs. 21%; P ¼.0036). There was clinically noteworthy, significant impairment of the ability to collect sufficient numbers of blood stem cells, as defined above, for subsequent ASCT among patients in the MCP arm who were age <60 years. After MCP, stem cells could be collected in only 44% of patients who were scheduled for ASCT, compared with 93% of patients after CHOP (P ¼.0003). Among nonhematologic side effects, mostly mild-tomoderate nausea was reported more frequently after CHOP than after MCP (41% vs. 31%; P ¼.0014). Moreover, peripheral neurotoxicity occurred more frequently after CHOP (35% vs. 4%; P <.0001). In addition, CHOP was

7 1020 CANCER September 1, 2006 / Volume 107 / Number 5 TABLE 4 Treatment Results from Combined Cyclophosphamide, Vincristine, Doxorubicin, and Prednisone versus Combined Mitoxantrone, Chlorambucil, and Prednisone: Hematologic Toxicities Toxicity CHOP, % MCP, % Significance (P) Anemia.66 WHO Grade WHO Grade Leukocytopenia.0003 WHO Grade WHO Grade Granulocytopenia.0041 WHO Grade WHO Grade Thrombocytopenia.0036 WHO Grade WHO Grade CHOP indicates cyclophosphamide, vincristine, doxorubicin, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone; WHO, World Health Organization. TABLE 5 Treatment Results from Combined Cyclophosphamide, Vincristine, Doxorubicin, and Prednisone versus Combined Mitoxantrone, Chlorambucil, and Prednisone: Nonhematologic Toxicities Toxicity CHOP, % MCP, % Significance (P) Mucositis.019 WHO Grade WHO Grade Fever.27 WHO Grade WHO Grade Infections.37 WHO Grade WHO Grade Nausea/emesis.0014 WHO Grade WHO Grade Diarrhea.22 WHO Grade WHO Grade Alopecia <.0001 WHO Grade WHO Grade Neurotoxicity <.0001 WHO Grade WHO Grade CHOP indicates cyclophosphamide, vincristine, doxorubicin, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone; WHO, World Health Organization. associated with a higher incidence of temporary alopecia (88% vs. 40%; P <.0001) (Table 5). DISCUSSION Whereas CHOP is a well established regimen in the treatment of malignant lymphomas, MCP is used less frequently. MCP was chosen for comparison with CHOP, because a preceding randomized trial of the GLSG revealed a higher CR rate and fewer side effects after MCP compared with COP. 14 Based on this background, the comparison of CHOP versus MCP revealed a significantly higher OR rate after CHOP in patients with FL (91% vs. 82%; P ¼.026) and a similar tendency in patients with MCL (87% vs. 73%; P ¼.080), but no difference was observed in TTF, RD, or OS. In terms of toxicity, CHOP was associated with a significantly higher incidence of nausea and emesis, peripheral neurotoxicity, and temporary alopecia; whereas MCP was associated with a higher rate of severe myelosuppression. These overall results are rather disappointing and add to the long list of unsuccessful attempts to improve on the long-term prognoses for patients with FL and MCL. 1,3,19 22 They demonstrate that remissions can be achieved in a large proportion of patients but that an improvement in remission rate does not translate into a prolongation of TTF, RD, or even OS. 23,24 In contrast, recent data clearly demonstrate that the addition of rituximab to chemotherapy (R-chemo) has a significant impact on response rates and long-term outcomes. Results from 5 prospective randomized trials, including 4 studies of R-chemo as first-line therapy and 1 study of R-chemo as salvage treatment, consistently have shown that R-chemo improves response rates and prolongsttfandrdcomparedwithchemotherapyalone. In 3 of those trials, even OS was significantly longer This is in agreement with a recent published analysis of patients with advanced-stage FL who were treated on Southwest Oncology Group Lymphoma Committee protocols 25. Hence, R-chemo has been accepted rapidly as standard treatment for patients with advanced-stage FL. However, the question remains unanswered whether the type of chemotherapy to be combined with rituximab is of importance and, if so, which regimen is most effective. The current trial of MCP versus CHOP may provide helpful information to approach this question. Table 6 provides an overview over the results of the 4 trials that compared R-chemo versus chemotherapy alone as firstline therapy for patients with advanced-stage FL and reveals substantial differences. For chemotherapy alone, CHOP appears to be the most active combination, with an OR rate of 90% compared with OR rates of 57% for CVP, 75% for MCP, and 74% for CHVP þ IFN, and a median response duration of 31 months compared with 15 months for CVP and 20 months for MCP. It certainly can be argued that these differences may have been caused by different inclusion criteria or different risk profiles in the patients studied. However, these results are in line with data from the current trial,

8 CHOP versus MCP in FL and MCL/Nickenig et al TABLE 6 Results of Rituximab Plus Chemotherapy versus Chemotherapy Alone as First-Line Therapy for Patients with Advanced Stage Follicular Lymphoma Regimen OR, % P PFS, Months P CVP 571 < <.001 R-CVP* CHOP R-CHOP y 96 NR MCP <.0001 R-MCP {10 92 NR CHVP þ IFN 74 <.0001 NR R-CHVP þ IFN 85 NR OR indicates overall response; PFS, progression-free survival; CVP, cyclophosphamide, vincristine, and prednisone; R-CVP, rituximab plus CVP; CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone; R-CHOP, rituximab plus CHOP; NR, not reached; MCP, mitoxantrone, chlorambucil, and prednisone; R-MCP, rituximab plus MCP; CHVP, cyclophosphamide, doxorubicine, vindesine, and prednisone; IFN, interferon; R-CHVP þ IFN, rituximab plus CHVP and IFN. * Marcus et al., y Hiddemann et al., { Herold et al., Salles et al., which revealed OR rates of 91% for CHOP and 82% for MCP. When analyzing the improvements achieved by the addition of rituximab, the greatest increase in response rates was observed for R-CVP (þ 24%), followed by R- MCP (þ17%). Nevertheless, the OR rate after R-CVP remains lower than after CHOP alone. In a comparison of those results, R-CHOP was the most effective immunochemotherapy with an OR rate of 96%. It must be emphasized that these considerations are speculative to a certain degree and are intended primarily to raise questions rather than to answer them and to generate hypotheses for future trials. However, they are supported by data from preclinical analyses, which demonstrated substantial differences in the efficacy of rituximab when it was combined with different antilymphoma agents. 26,27 A subgroup analysis of the patients in the current trial who were scheduled to undergo subsequent myeloablative radiochemotherapy and ASCT showed that MCP was more toxic to hematopoietic stem cells than CHOP, because stem cell mobilization was possible in only 44% of patients after MCP compared with 93% after CHOP. Furthermore, as reported previously, the 5-year risk of developing a secondary hematologic neoplasia after myeloablative therapy and ASCT was 5.1% in patients who received MCP compared with only 1.3% after CHOP. 28 Based on these data, the GLSG has embarked on a prospective, randomized comparison of R-MCP versus R-CHOP versus rituximab combined with fludarabine, cyclophosphamide, and mitoxantrone; however, that trial has been restricted trial to older patients who are not suitable for myeloablative radiochemotherapy with subsequent ASCT. In younger patients, R-CHOP is used as the baseline regimen for all patients, and there is a subsequent randomization for ASCT followed by rituximab maintenance versus rituximab maintenance alone. This strategy is supported by the finding that the beneficial effect of CHOP over MCP was particularly high in patients age <60 years (89% vs. 78%; P ¼.011). 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