(R-CHOP) Results in a Higher Response Rate and Longer

The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG)

C Buske1, E Hoster1,2, M Dreyling1, H Eimermacher3, H Wandt4, B Metzner5, R Fuchs6, J Bittenbring7, B Woermann8, K Hohloch9, G Hess10, W-D Ludwig11, J Schimke12, S Schmitz13, M Kneba14, M Reiser15, U Graeven16, W Klapper17, M Unterhalt1 and W Hiddemann1

1Department of Internal Medicine III, University of Munich, Campus Grohadern, Munich, Germany; 2Department of Medical Informatics, Biometry and Epidemiology (IBE), University of Munich, Munich, Germany; 3Department of Medicine II, Catholic Hospital Hagen, Hagen, Germany; 4Department of Medicine 5, Hospital Nuernberg North, Nuernberg, Germany; 5Department of Medicine II, Klinikum Oldenburg, Oldenburg, Germany; 6Department of Hematology/Oncology, St Antonius Hospital, Eschweiler, Germany; 7Department of Medicine I, University Medical School Saarland, Homburg, Germany; 8Department of Medicine, City Hospital Braunschweig, Braunschweig, Germany; 9Department of Hematology/Oncology, Georg-August- University, Goettingen, Germany; 10Department of Internal Medicine III, Johannes-Gutenberg-University, Mainz, Germany; 11Robert-Ro¨ssle-Clinic at the HELIOS Clinic Berlin-Buch, Charite´, Campus Buch, Berlin, Germany; 12Practice for Hematology/ Oncology, Saarbruecken, Germany; 13Practice of Hematology/Oncology, Koeln, Germany; 14Department of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 15Department of Internal Medicine I, University of Cologne, Cologne, Germany; 16Department of Hematology and Oncology, Kliniken Maria Hilf, Mo¨nchengladbach, Germany and 17Department of Haematopathology and Lymph Node Registry Kiel, Schleswig-Holstein University Hospitals, Campus Kiel, Kiel, Germany

Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma is described as a rare indolent CD20-positive B-cell lymphoma, with moderate sensitivity to conventional chemotherapy. This which is characterized by elements ranging from small study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL lymphocytes, lymphoplasmacytoid forms to mature plasma and the subgroup of LPL patients fulfilling the criteria of cells. A subgroup of LPL patients represents with monoclonal Waldenstroem’s macroglobulinemia (WM). A total of 69 patients immunoglobulin M (IgM) paraproteinemia and bone marrow with previously untreated LPL were enrolled into the trial; 64 involvement. These cases irrespective of the IgM serum patients were evaluable for treatment outcome. In all, 48 of the concentration are defined as Waldenstroem’s macroglobuline- 64 LPL patients fulfilled the criteria of WM. Patients were mia (WM). WM is considered to be a distinct clinicopatholo- randomly assigned to R-CHOP (rituximab, cyclophosphamide, gical entity and often presents with typical clinical symptoms, doxorubicin, vincristine and prednisone, n ¼ 34) or CHOP (n ¼ 30). R-CHOP resulted in significantly higher overall res- such as peripheral neuropathy or hyperviscosity syndrome, 2–4 ponse (OR) rate (94 vs 67%, P ¼ 0.0085) in the LPL patients and associated with IgM monoclonal gammopathy. There are in the WM subgroup (91 vs 60%, P ¼ 0.0188). With a median only few clinical studies reported in LPL: in a retrospective observation time of 42 months, R-CHOP induced a significantly analysis treatment outcome was analyzed in 126 patients with longer time to treatment failure (TTF) with a median of 63 immunocytoma according to the Kiel classification, including months for R-CHOP vs 22 months in the CHOP arm in the LPL 24 patients with lymphoplasmacytic histology. In all, 13 of the patients (P ¼ 0.0033) and in the WM subgroup (P ¼ 0.0241). There was no major difference of treatment-associated toxicity 24 patients with lymphoplasmacytic histology were classified as between both treatment groups. These data indicate that the WM. Patients were treated with various chemotherapy regimens addition of rituximab to front-line chemotherapy improves including cyclophosphamide, vincristine and prednisone treatment outcome in patients with LPL or WM. (CVP)-, doxorubicin- or fludarabine-containing regimens be- Leukemia (2009) 23, 153–161; doi:10.1038/leu.2008.261; tween 1972–1996, but only incomplete responses of short published online 25 September 2008 5 Keywords: lymphoplasmacytic lymphoma; waldenstroem’s duration were documented. In contrast to LPL, multiple phase II macroglobulinemia; rituximab; immunochemotherapy studies tested the efficacy of chemotherapy in WM: the standard front-line therapy in WM has been the use of alkylating agents or purine analogs, such as chlorambucil or fludarabine, respectively. However, the clinical activity of these compounds is Introduction limited: in a meta-analysis of 217 patients with WM treated with mostly chlorambucil, the overall response (OR) rate was 48% In the current World Health Organization (WHO) classification, 6 with a complete remission (CR) rate of 2%. In a large lymphoplasmacytic lymphoma (LPL), the former immuno- nonrandomized study, fludarabine single-agent therapy induced cytoma of the lymphoplasmacytic type in the Kiel classification,1 a response in 36% of 182 patients with WM and a CR in 2% of cases.7 In a randomized trial, fludarabine was significantly Correspondence: Professor C Buske, Department of Medicine III, superior to a combination therapy of cyclophosphamide, University of Munich, Campus Gro hadern, Marchioninistr. 15, doxorubicin and prednisone with a response duration of 19 vs Mu¨nchen 81377, Germany. E-mail: [email protected] 3 months in 92 patients with relapsed or primary refractory 8 Received 24 June 2008; revised 30 July 2008; accepted 12 August disease. In a phase II study, analyzing 49 patients, the 2008; published online 25 September 2008 combination of fludarabine and cyclophosphamide achieved R-CHOP in LPL C Buske et al 154 an OR of 77.6% and a median time to treatment failure (TTF) vincristine 1.4 mg/m2 (max. 2.0 mg/day) i.v. on day 1 and of 27 months.9 All these data underline that conventional prednisone 100 mg/m2 orally on days 1–5. Treatment cycles chemotherapy is effective in LPL and WM, but to a limited were repeated every 3 weeks for a total of four to eight cycles. At extent. CD20 is strongly expressed on most of the cells in LPL signs of neuropathy, application of vincristine was stopped in and WM forming a rationale to incorporate the anti-CD20 the subsequent cycles. Patients who were randomized into the antibody rituximab into the therapy of this disease. Clinical trials R-CHOP arm received a dose of 375 mg/m2/day rituximab on on the efficacy of single- agent therapy in WM showed an OR the day before the respective CHOP course. up to 48%.10 However, CR rates were low and the responses of After the first two cycles of initial cytoreduction, patients o60 short duration in the majority of patients. So far, there are no years of age were offered a second randomization for treatment data from randomized phase III trials about the efficacy of in remission to either myeloablative therapy followed by rituximab/chemotherapy combinations in patients with LPL or autologous stem cell transplantation or long-term interferon-a WM, proven to be highly effective in follicular and other B-cell (IFN-a) maintenance. In the autologous stem cell transplantation lymphomas.11–13 On the basis of a multicenter randomized trial (ASCT) arm, high-dose therapy consisted of intensification by initiated by the German Low-Grade Lymphoma Study Group the Dexa-BEAM regimen comprising dexamethason 3 Â 8mg (GLSG), we now demonstrate that R-CHOP (rituximab, cyclo- orally on days 1–10, BCNU 60 mg/m2/day on day 2, melphalan phosphamide, doxorubicin, vincristine and prednisone) signi- 20 mg/m2/day i.v. on day 3, etoposide 75 mg/m2/day i.v. on days ficantly improves the response and TTF in previously untreated 4–7 and cytosine arabinoside 2 Â 100 mg/m2 every 12 h. i.v. on patients with LPL and WM compared with CHOP alone. days 4–7 with subsequent stem cell harvest followed by myeloablative radiochemotherapy with total body irradiation (12 Gy) and cyclophosphamide 60 mg/kg/day for 2 days and Patients and methods stem cell retransfusion. Patients responding to induction therapy started long-term Patients and entry criteria IFN-a maintenance at a dose of three times 5 Â 106 U/week. All This study was performed as a randomized, open-label multi- patients aged 60 years or above received IFN-a maintenance if center phase III trial. It was started in 2000 and included patients they at least achieved a partial remission (PR) after initial four to at the age of 18 years and above with previously untreated six induction cycles of CHOP or R-CHOP. IFN-a maintenance advanced stage follicular lymphoma (FL), mantle cell lymphoma therapy was given until lymphoma progression or the develop- (MCL) and immunocytoma of the lymphoplasmacytic and ment of intolerable side effects. lymphoplasmacytoid type according to the Kiel1 classification. The number of initial chemotherapy cycles depended on the Randomization was stratified for histology, and the results of response after four courses and planned postremission therapy. patients with FL and MCL have been reported previously.11,14 Induction therapy was stopped in patients achieving a CR after Here, we report the results for patients with LPL according four cycles, when they were randomized for myeloablative to the WHO classification corresponding to the immunocytoma therapy followed by an ASCT. In all other patients, six cycles of of the lymphoplasmacytic type of the Kiel classification. Our induction were planned. Patients assigned to IFN maintenance analysis included patients with WM defined according to the received two additional cycles of the initial cytoreductive criteria of the second Waldenstroem’s workshop recommenda- regimen to balance the mobilization scheme (Dexa-BEAM) in tions with the diagnosis of LPL, the presence of a monoclonal the ASCT arm before starting long-term IFN-a maintenance. IgM on immunoelectrophoresis or immunofixation irrespective Thus, patients who achieved a PR after six cycles of initial of IgM serum concentration and bone marrow involvement.15 therapy received a maximum of eight cycles of cytoreduction. Eleven additional patients with lymphoplasmacytoid immuno- Patients with progressive disease at any time during CHOP or cytoma according to the Kiel classification, which is now R-CHOP therapy or stable disease after four to six cycles were considered to be a B-CLL variant in the WHO classification, taken off study. were excluded from the analysis. The histologic diagnosis was confirmed by central review at one of the six designated pathology reference centers. Evaluation and response criteria Clinical entry criteria comprised stage III or IV disease and a Response to therapy was assessed 3 weeks after every two cycles requirement for therapeutic intervention as defined by the of CHOP or R-CHOP, respectively, and 4 weeks after the presence of B-symptoms and/or bulky disease (mediastinal mass completion of last course. Response evaluation comprised a 47.5 cm, or other nodal mass 45 cm in its greater diameter) physical examination, the determination of blood counts, lactate and/or an impairment of normal hematopoesis (granulocyto- dehydrogenase (LDH), IgM serum levels and an ultrasound penia o1.500/ml, Hb o10 g per 100 ml, thrombocytopenia of the abdomen and CT scans of previously involved areas. In o100 000/ml) and/or a rapidly progressive disorder, including patients with initial bone marrow involvement fulfilling other- symptomatic neuropathy or cryroglobulinemia. wise the criteria of a CR, a bone marrow biopsy was performed. The initial diagnostic work-up comprised the assessment of For the follow-up, the aforementioned analyses were the extent of the disease including bone marrow biopsy, performed every 3 months except for CT scans of previously ultrasound examination of the abdomen and CT scans of chest involved areas, which were repeated every 6 months. and abdomen. Furthermore, the presence of monoclonal IgM Response was defined according to the International Working gammopathy was tested by immunoelectrophoresis and/or Group criteria and retrospectively at the time point of this immunofixation. analysis in patients fulfilling the criteria of WM according to the second Waldenstroem workshop.16,17 Hence, the CR comprised the elimination of all lymphoma manifestations for at least Randomization and treatment protocol 4 weeks including the bone marrow and disappearance of the Patients were initially randomized between induction therapy monoclonal protein in the serum, whereas PR was defined as with CHOP or R-CHOP. The CHOP combination comprised a reduction of disease manifestations by at least 50% for more cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., than 4 weeks including the IgM serum level tested by

Leukemia R-CHOP in LPL C Buske et al 155 electrophoresis. In modification of the aforementioned criteria, international prognostic index (FLIPI),18 and mantle cell the category of unconfirmed CR was not used. Instead, patients lymphoma international prognostic index (MIPI)19 and for LPL who fulfilled CR criteria, but in whom bone marrow biopsy was patients’4,20 age, ECOG (Eastern Cooperative Oncology Group) not evaluable, were counted as PR. The appearance of new performance status, LDH (quotient to upper limit of normal), nodal or extranodal manifestations, the enlargement of preexist- hemoglobin, white blood cell count, platelet count, number of ing lymphoma manifestations or an increase of IgM serum levels involved nodal areas and sex. by more than 25% were considered as progression. In the cohort of LPL patients, the effect of treatment was Overall response (OR) was the achievement of CR or PR. adjusted for the prognostic factors age, hemoglobin and platelet Time to treatment failure was defined as the interval between count in multiple Cox regression. Interaction effects were the start of treatment and the documentation of resistance to estimated for assignment to IFN maintenance and WM initial therapy, progressive disease or death from any cause. The diagnosis, separately, and treatment effect subsequently ad- median observation time for TTF was calculated for patients justed for assignment to IFN maintenance or WM diagnosis, without failure. Overall survival was defined as the interval respectively. between start of treatment and death from any cause. Analyses All analyses were two-sided on a significance level of were performed on an intention-to-treat basis without censoring a ¼ 0.05. for patients refusing the scheduled treatment in remission or receiving other unplanned therapies. Study conduct The frequency and severity of side effects was recorded The study was carried out in accordance with the modified according to the WHO toxicity criteria. Helsinki declaration. Before initiation, the study received approval by the responsible ethic committees. All patients gave written informed consent before participating in the trial. Statistics Time to treatment failure was defined as the primary statistical end point of this study for the indolent lymphomas included in Results this study (FL and LPL). The comparison of CHOP alone with R-CHOP was designed to test whether the addition of rituximab Characteristics of patients with LPL could reduce the risk for treatment failure in FL by 50% Between June 2000 and August 2003, a total of 70 patients with according to a proportional hazards assumption. On this basis, a LPL were enrolled into the trial. A total of 69 cases were one-sided triangular sequential test for log-rank analysis with a randomized between R-CHOP and CHOP with 64 patients being working significance level of 0.01 was applied. This procedure evaluable for treatment outcome. The median age was 61 years allowed for the detection of the assumed superiority of R-CHOP ranging from 37 to 78 years. All patients had stage III/IV disease over CHOP alone with a probability of 95% in FL patients. The and were in need of therapy. In all, 48 of the 64 LPL cases fulfilled sequential procedure was designed to be equivalent in power the criteria of WM with the histological diagnosis of LPL, bone and working significance level to a fixed sample test with 148 marrow involvement and the presence of monoclonal serum IgM. observations. In this WM patient group, the median age was also 61 years with Lymphoplasmacytic lymphoma patients were included in the a range from 37 to 78 years. The median hemoglobin, IgM and trial as the same clinical question was posed for this entity. b2-microglobulin levels were 97 g/l, 34 g/l and 2.9 mg/l, respec- However, because of the lower incidence of LPL, no formal tively. Table 1 summarizes the main characteristics of patients sample size calculation was performed for this entity, and with LPL, including the subgroup of patients with WM, indicating randomization was closed for LPL patients together with the FL a balanced distribution between the two treatment arms. Figure 1 patients. shows the patients’ flow of the trial. After randomization was completed, further secondary analysis was performed of CR and overall response rate, duration of response, overall survival and safety using the Fisher Treatment exact test for binary responses and the log-rank test and A total of 34 patients with LPL were randomized into the univariate Cox regression analysis for time-censored observa- R-CHOP arm, 30 patients received CHOP chemotherapy. Six tions. Efficacy comparisons were performed strictly according to patients of the R-CHOP arm and four patients of the CHOP arm the intention to treat. were assigned to ASCT, the remaining 28 R-CHOP and 26 Categorical baseline characteristics were compared with the CHOP patients were assigned to IFN maintenance. In the group Fisher’s exact test, numerical baseline characteristics with the of patients classified as WM, 23 patients were treated with Mann–Whitney-U-test. R-CHOP, 25 patients received CHOP. 52 of the patients with Multiple Cox regression for TTF was performed to assess LPL (32 patients after R-CHOP and 20 patients after CHOP) interaction effects between treatment and histology and to adjust achieved a CR or PR, and were therefore evaluable for for prognostic factors. All interaction analyses first included the postremission therapy. The majority of patients started IFN-a main effects together with the interaction term. In further maintenance (20 after R-CHOP, 13 of these with WM, 10 after adjusted analyses, the interaction term was only included if CHOP six with WM); in 14 patients (11 with WM), no further previously significant. treatment was applied (seven after R-CHOP and seven after In the complete cohort of the trial, including patients with CHOP). Only eight patients finally received intensification advanced stage LPL, FL and MCL, the interaction terms of followed by myeloablative radiochemotherapy and ASCT: Five histology (LPL vs FL vs MCL) with treatment (randomization to (three with WM) patients after R-CHOP and three (all with WM) R-CHOP vs CHOP) were assessed in a model together with the patients after CHOP. Thus, 84% of the responding patients in the main effects, histology and treatment. As no significant R-CHOP arm compared with 85% in the CHOP arm received interaction was observed, the main effects of histology and IFN-a maintenance or no further therapy, demonstrating a treatment were then adjusted for prognostic factors. We used the balanced distribution of postremission therapy in the two following known prognostic factors of follicular lymphoma treatment groups (Table 2).

Leukemia R-CHOP in LPL C Buske et al 156 Table 1 Patient characteristics with LPL and the subgroup of patients with WM

Parameter Value N R-CHOP: N R-CHOP: % or CHOP: or N CHOP: % or P-value or median min-max median min-max

(A) LPL Age Years 64 59 40–78 62 37–74 0.27 Sex Male 64 17 50 23 77 0.039 Stage IV 64 33 97 29 97 1.00 Nodal areas 44 63 9 27 10 33 0.78 extranodal sites 41 64 4 12 3 10 1.00 Bone marrow Involved 64 32 94 28 93 1.00 B symptoms Present 62 12 38 14 47 0.61 ECOG 0 63 8 24 7 24 1.00 123681966 239310 WBC Per ml 64 6100 1047–1 13 000 6350 1900–21 300 0.88 Lymphocyte count Per ml 60 2002 481–39 900 1600 240–15 826 0.61 Platelet count Per ml 64 2 12 500 25 000–8 50 000 2 14 500 73 000–6 21 000 0.43 LDH 4ULN 64 6 18 4 13 0.74 Hemoglobin g/l 64 108 48–144 96 49–164 0.39 b2-Microglobulin mg/l 41 2.6 0.3–10.5 3.0 1.6–11.5 0.30

(B) WM Age Years 48 58 40–78 62 37–74 Sex Male 48 15 65 20 80 Stage IV 48 23 100 25 100 Nodal areas 44 47 6 27 9 36 extranodal sites 41482 9 2 8 Bone marrow Involved 48 23 100 25 100 B symptoms Present 46 8 38 13 52 ECOG 0 48 4 17 4 16 117741872 228312 WBC Per ml 48 4800 1047–42 400 6000 1900–15 300 Lymphocyte count Per ml 46 1450 639–39 900 1517.5 240–9180 Platelet count Per ml 48 210000 25 000–8 50 000 2 24 000 73 000–6 21 000 LDH 4ULN 48 3 13 3 12 Hemoglobin g/l 48 97 48–144 93 49–139 IgM* g/l 47 37.2 3.3–111 31.6 4.2–88 b2-Microglobulin mg/l 32 2.5 0.3–10.5 3.0 1.6–11.5 Abbreviations: ECOG, Eastern Cooperative Oncology Group; IgM, immunoglobulin M; LDH, Lactate dehydrogenase; LPL, lymphoplasmacytic lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; ULN: upper limit of normal; n: number of evaluable patients; WBC, white blood cell; WM, Waldenstroem’s macroglobulinemia. *From one patient with WM IgM serum concentration was not available.

Efficacy In LPL patients, multiple regression analysis, including The addition of rituximab to CHOP resulted in a significantly age, hemoglobin and platelet count, did not result in a smaller higher OR rate of 94 vs 67% in patients with LPL (95% CI, 80– risk reduction (hazard ratio, 0.29, 0.13–0.64) comparing TTF 99 vs 47–83%, P ¼ 0.0085). However, there was no significant according to randomization to R-CHOP or CHOP. Similar difference in the CR rate between the two treatment arms (9%, results as in the cohort of patients with LPL were observed in the 95% CI 2%–24 vs 7%, 95% CI 1–22%, P ¼ 1). Two patients subgroup of 48 evaluable WM patients: In the R-CHOP arm, a experienced progressive disease after CHOP compared with significantly higher OR rate of 91% (95% CI 72–99%) vs 60% none after R-CHOP (Table 3). With a median observation time (95% CI 39–79%) for CHOP alone was observed (P ¼ 0.0188), of 42 months, 12 patients on the R-CHOP arm experienced a whereas the CR rates were not statistically different (9%, 95% CI treatment failure as compared with 19 patients treated with 1–28% vs 4%, 95% CI 0–20%, P ¼ 0.60). R-CHOP led to a CHOP alone. The median TTF was 63 months vs 22 months significantly longer TTF with a median 63 months for R-CHOP (P ¼ 0.0033; Figure 2a). The probability of failure-free survival at vs 22 months in the CHOP arm (P ¼ 0.0241; Figure 2b) 2 years was 0.49 (95% CI 0.30–0.66) for CHOP, compared with (probability of failure-free survival at 2 years are 0.47 (95% 0.85 (95% CI 0.67–0.93) for R-CHOP. CI 0.26–0.65) and 0.78 (95% CI 0.54–0.90) for CHOP and The hazard ratio for TTF (0.35, 95% CI 0.17–0.73) was not R-CHOP, respectively). substantially different to the values seen in follicular (0.38, No significant interaction term of clinical diagnosis of WM to 0.29–0.50, n ¼ 553) or MCL (0.49, 0.33–0.73, n ¼ 127), or the the treatment effect was observed (P ¼ 1.0), and adjustment for whole patient cohort (0.42, 0.34–0.53, n ¼ 744, Figure 3). No WM diagnosis did not change the hazard ratio for TTF (0.38, significant interaction between the effect of randomization to R- 0.18–0.82). CHOP or CHOP and histology could be detected (P ¼ 0.73 FL vs When the analysis for TTF was restricted to patients assigned LPL, P ¼ 0.37 MCL vs LPL). The effect of randomization between to IFN maintenance or no further therapy to exclude the possible R-CHOP and CHOP in the complete cohort of LPL, FL and MCL impact of ASCT in the first remission on this parameter, patients was similar adjusted for histology (0.41, 0.33–0.50) and differences between R-CHOP vs CHOP remained statistically for histology and prognostic factors (0.40, 0.33–0.50). significant in the LPL as well as WM group.

Leukemia R-CHOP in LPL C Buske et al 157 70 LPL patients enrolled

1 refused rituximab

69 randomized

36 randomized to 33 randomized to R-CHOP CHOP

2 insufficient 1 restaging not done 2 insufficient documentation documentation

34 analyzed 30 analyzed

8 no monoclonal IgM 3 no monoclonal IgM 2 not evaluable for 1 not evaluable for monoclonal IgM monoclonal IgM 1 no BM involvement 1 no BM involvement

23 WM 25 WM

LPL, lymphoplasmacytic lymphoma

WM, Waldenstrom’s macroglobulinemia

Figure 1 Flow of 70 patients with LPL enrolled into the clinical trial. LPL, lymphoplasmacytic lymphoma.

Table 2 Postremission therapy Table 3 Response to R-CHOP and CHOP

R-CHOP % CHOP % P-value R-CHOP % CHOP % P-value (N) (N) (N) (N)

(A) LPL (A) LPL Patients evaluable 32 20 Patients 34 30 Postremission therapy Remission IFN maintenance 20 63 10 50 0.53 OR (95% CI) 32 94 (80–99) 20 67 (47–83) 0.0085 No further tx 722735 CR 3 9 2 7 1.0 ASCT 5 16 3 15 PR 29 85 18 60 SD 2 6 8 27 (B) WM PD0 027 Patients evaluable 21 15 Death 0 0 0 0 Postremission therapy IFN maintenance 13 62 6 40 0.49 (B) WM No further tx 524640 Patients 23 25 ASCT 3 14 3 20 Remission OR (95% CI) 21 91 (72–99) 15 60 (39–79) 0.0188 Abbreviations: ASCT, autologous stem cell transplantation; IFN, CR 2 9 1 4 0.60 interferon; LPL, lymphoplasmacytic lymphoma; R-CHOP, rituximab, PR 19 83 14 56 cyclophosphamide, doxorubicin, vincristine and prednisone; SD 2 9 8 32 tx, therapy; WM, Waldenstroem’s macroglobulinemia. PD0 028 Death 0 0 0 0 Abbreviations: CI, conﬁdence interval; CR, complete remission; LPL, No signiﬁcant interaction term of assignment to IFN main- lymphoplasmacytic lymphoma; OR, overall response; PD, progressive tenance with the treatment effect was observed (P ¼ 0.33), and disease; PR, partial remission; R-CHOP, rituximab, cyclophosphamide, adjustment for assignment to IFN maintenance did not change doxorubicin, vincristine and prednisone; SD, stable disease; WM, the hazard ratio for TTF (0.35, 0.17–0.72). Waldenstroem’s macroglobulinemia.

Leukemia R-CHOP in LPL C Buske et al 158

Figure 2 Time to treatment failure after the start of therapy for CHOP or R-CHOP for patients with LPL (a)orWM(b). The number of patients at risk is indicated. LPL, lymphoplasmacytic lymphoma; WM, Waldenstroem’s macroglobulinemia.

All five patients in the ASCT group who had achieved Side effects a PR after R-CHOP induction achieved a CR after ASCT, Treatment-associated hematologic side effects comprised pre- whereas all three patients in the CHOP arm remained in dominantly myelosuppression and granulocytopenia (Table 4). PR after ASCT. Three patients relapsed after ASCT, one in Granulocytopenia of grades 3 and 4 occurred after 72% of the CHOP group, after 18 months and two in the R-CHOP R-CHOP-treated patients as compared with 57% of CHOP- group, after 9 and 41 months. There was no death in remission treated patients (P ¼ 0.58). This difference was clinically of so far. minor relevance, however, as grade 3/4 infections were At this time, the observation period is still relatively short for encountered in 6% after R-CHOP compared with 13% after an assessment of overall survival. So far, 10 of the 64 LPL CHOP (P ¼ 0.58). patients died, seven patients in the CHOP arm compared with Nonhematological side effects consisted mainly of alopecia, three in the R-CHOP arm (P ¼ 0.11; Figure 4). In the subgroup of nausea and vomiting, which occurred at similar frequencies WM patients, 7 of 48 patients evaluable for overall survival after both regimens. The toxicity in the subgroup of patients died, five patients in the CHOP arm compared with two in the classified as WM was similar to the whole cohort of LPL R-CHOP arm (P ¼ 0.28). patients.

Leukemia R-CHOP in LPL C Buske et al 159 Discussion viral infections.21 In another small series, five of nine evaluable patients with WM achieved a PR with rituximab/fludarabine/ So far, conventional chemotherapy has shown only limited cyclophosphamide.22 In another phase II study, 72 patients with activity in patients with LPL or WM. In an effort to improve WM were treated front line with dexamethasone 20 mg i.v. treatment outcome, Treon et al.21 added rituximab to fludar- followed by rituximab 375 mg/m2 i.v. on day 1 and cyclo- abine in 43 evaluable patients with previously treated WM in phosphamide 100 mg/m2 p.o. b.i.d. days 1–5 for a total of six a phase II study: immunochemotherapy induced a partial courses repeated every 21 days: 83% of the patients responded response in 35 patients with three patients achieving a CR. (7% CR, 67% PR and 9% minor responses) with a 2-year Response duration was encouraging with 36 of the 39 remaining progression-free survival of 67%. This regimen well tolerated in remission after a median follow-up of 17 months. However, with the exception of one patient, who died of interstitial toxicity was considerable with several patients experiencing pneumonia.23 Taken together, these first experiences with grade III/IV neutropenia with subsequent delay of treatment or rituximab/chemotherapy combinations in the treatment of WM suggested a high antilymphoma activity coupled with a tolerable toxicity profile. We now confirmed the efficacy of immunochemotherapy in a multicenter phase III study with significantly improved OR rates and prolongation of the TTF after R-CHOP induction compared with CHOP alone in previously untreated patients with LPL. The superiority of R-CHOP could be confirmed in the subgroup analysis of patients with WM, with an OR rate of 91 vs 60% and median TTF of 63 vs 22 months, although data have to be taken with caution because the sample size in our analyses was small. Importantly, in a situation of a noncurative disease occurring in patients mostly of advanced age, we did not see any additional toxicity in the R-CHOP arm compared wth CHOP alone. These data of a multicenter prospective randomized study are remarkable in particular for patients with WM with an OR rate above 90% and a median TTF of over 5 years. Despite the encouraging results of R-CHOP in this trial, the CR rate was moderate with a CR in 2 of 25 patients, only. These data are in line with previous reports from phase II studies, demonstrating the difficulties to induce a CR in patients with LPL and WM even after rituximab/chemotherapy.21,23 One strategy to further improve the treatment outcome might be a Figure 3 Forest plot visualizing the TTF after R-CHOP vs CHOP dose-intensive consolidation, such as myeloablative radio- according to the histological entities, such as LPL, FL and MCL. chemotherapy, followed by an ASCT in the first remission. This Hazard ratios for TTF with 95% confidence intervals are shown. The width of the box is proportional to the sample size. LPL, lympho- concept was shown to improve the response quality in patients plasmacytic lymphoma; FL, follicular lymphoma; MCL, mantle cell with advanced stage FL, increasing the proportion of patients lymphoma; TTF, time to treatment failure. in CR from 19.3% after CHOP or MCP (mitoxantrone,

Figure 4 Overall survival (OS) after the start of therapy for CHOP or R-CHOP for patients with LPL. The number of patients at risk is indicated. LPL, lymphoplasmacytic lymphoma.

Leukemia R-CHOP in LPL C Buske et al 160 Table 4 Side effects after R-CHOP vs CHOP in LPL patients Although our analysis is among very few randomized evaluated as treated comparisons reported for LPL and WM, the data are based on a relatively small subgroup originating from a large randomized Category Grade Percentage Percentage P-value trial. However, in our trial, subgroup analysed according to the of R-CHOP of CHOP lymphoma entities were stabilized by stratified randomization. N ¼ 36 N ¼ 33 Furthermore, no substantial differences in baseline charac- WBC Grade I/II 28 34 0.62 teristics could be observed between the treatment arms in LPL Grade III/IV 69 59 patients. Analyses adjusted for known prognostic factors as Granulocytes Grade I/II 14 19 0.58 potential confounders did not change the observed effects. In Grade III/IV 72 57 addition, the hazard ratios for TTF observed in LPL patients were Platelets Grade I/II 20 31 0.61 similar to the results in the complete cohort of LPL, FL and MCL Grade III/IV 9 7 patients, as well as to the other subgroups, FL and MCL, and no Hemoglobin Grade I/II 61 43 0.29 Grade III/IV 22 39 significant interaction effect between histology and treatment Infection Grade I/II 25 20 0.58 could be detected. Thus, these data indicate that the results Grade III/IV 6 13 observed for LPL patients are qualitatively comparable to those Fever Grade I/II 28 37 0.35 already seen in FL and MCL patients,11,14 justifying the subgroup Grade III/IV 0 3 analyses for these separate lymphoma entities.31 Bleeding Grade I/II 6 6 1.00 Taken together, our data indicate that in patients with LPL and Grade III/IV 0 0 Mucositis Grade I/II 36 27 0.44 WM, the addition of rituximab to a polychemotherapy, such as Grade III/IV 0 0 CHOP, can significantly improve OR rates as well as TTF Nausea/vomiting Grade I/II 36 53 0.31 compared with chemotherapy alone. These results establish Grade III/IV 11 3 R-chemotherapy as a highly attractive concept for the first-line Diarrhea Grade I/II 6 7 0.86 treatment of these distinct lymphoma subtypes. However, Grade III/IV 8 3 further studies have to clarify whether other rituximab/ Constipation Grade I/II 11 13 1.00 Grade III/IV 6 3 chemotherapy combinations, for example, rituximab in combi- Alopecia Grade I/II 16 38 0.15 nation with purine analogues, such as fludarabine, will be Grade III/IV 66 48 superior to R-CHOP in these lymphoma entities. Heart function Grade I/II 0 10 0.09 Grade III/IV 0 0 Arrhythmia Grade I/II 0 10 0.09 Grade III/IV 0 0 Acknowledgements Neuropathy Grade I/II 43 45 0.71 Grade III/IV 0 3 This study was supported by the Deutsche Krebshilfe (T14/96/Hi CNS Grade I/II 6 7 1.00 1) and the Deutsches Bundesministerium fu¨r Bildung und Familie Grade III/IV 3 0 as part of the Competence Network Malignant Lymphomas. The Allergy Grade I/II 11 0 0.12 following participating persons and institutions recruited patients Grade III/IV 0 0 into the study. Abbreviations: LPL, lymphoplasmacytic lymphoma; R-CHOP, Gensicke, Dravoj, Stadtkrankenhaus Arolsen; Langer, Meusner, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; Ubbo-Emmius-Klinik, Aurich; Ludwig, Matylis, Robert-Ro¨ssle- WBC, white blood cell; WM, Waldenstroem’s macroglobulinemia. Klinic, Charite´, Campus Buch; Weh, Angrick, Franziskus Hospital, Bielefeld; Schmiegel, Graeven, Universita¨tsklinik Bochum; Musch, Ro¨hl, Mann, Marien-Hospital Bottrop; Wo¨rmann, Jordan, Pies, Sta¨dtisches Klinkum Braunschweig; Obst, Praxis, Burgwedel; chlorambucil and prednisolone) to 52.1%.24 In this series, Lohmann, Krankenhaus Coesfeld; von Gru¨nhagen, Praxis, Cott- mostly because of the age (460 years) of the patients at study bus; Kleinsorge, Praxis, Detmold; Becker, Meier, Hans Susemil entry, only eight patients received myeloablative radioche- Krankenhaus, Emden; Fuchs, Wehle-Ilka, St-Antonius-Hospital, motherapy followed by ASCT. Because of the very small size of Eschweiler; Eckert, Graeter, Sta¨dt. Kliniken, Esslingen; Massner, this subgroup no definite conclusions can be drawn. However, Praxis, Frankenthal; Mertelsmann, Finke, Universita¨tsklinik Frei- in all patients, this treatment concept was feasible, in line with burg i. Br.; Schliesser, Praxis, Giessen; Tru¨mper, Gla, Binder, other reports on a small number of mostly pretreated patients Universita¨tsklinik Go¨ttingen; Eimermacher, Lindemann, Kath. with WM receiving high-dose therapy and autotransplants.4,25 Krankenhaus, Hagen; Hurtz, Rohrberg, Schmidt, Praxis, Halle/ Further studies will have to show whether dose-intensive Saale; Bracht, Behn, St Sixtus-Hospital, Haltern Am See; Zander, approaches, such as ASCT, are indeed able to improve the Kro¨ger, Renges, Universita¨tsklinik Hamburg; Mu¨ller, Klinikum long-term perspective of this patient group. Another attractive Nord, Hamburg; Henne, Praxis, Hechingen; Freier, Praxis, approach is the concept of maintenance. IFN maintenance as Hildesheim; Pfreundschuh, Universita¨tsklinik Homburg/Saar; applied in this study was shown to be able to improve the Ho¨ffken, Fricke, Wedding, Universita¨tsklinik Jena; Kneba, Uni- progression-free survival in patients with FL compared with a versita¨tsklinik Kiel; Hallek, Reiser, Universita¨tsklinik Ko¨ln; watch and wait strategy. However, IFN maintenance is Schmitz, Steinmetz, Praxis, Ko¨ln; Mu¨ller, Praxis, Leer; Aldaoud, hampered by side effects forcing a substantial portion of patients Schwarzer, Praxis, Leipzig; Halm, Park-Krankenhaus, Leipzig; to reduce dosages.26–28 An alternative would be rituximab Wagner, Peters, Universita¨tsklinik Lu¨beck; Huber, Fischer, He, maintenance avoiding treatment-related toxicity associated with Universita¨tsklinik Mainz; Graeven, Kohl, Verbeek, Kliniken IFN application mostly in elderly patients with LPL or WM. Maria Hilf, Mo¨nchengladbach; Berdel, Universita¨tsklinik Mu¨nster; But so far, there is no major experience with rituximab Hutzschenreuter, Praxis, Nordhorn; Wilhelm, Wandt, Lechner, maintenance strategies after successful induction in patients Klinikum Nu¨rnberg, Nu¨rnberg; Bo¨ck, Ballo, Praxis, Offenbach; with LPL or WM, previously shown to be highly efficient in Henning-Ko¨hne, Metzner, Klinikum Oldenburg, Oldenburg; patients with relapsed FL.29,30 Andreesen, Krause, Mayer, Universita¨tsklinik Regensburg;

Leukemia R-CHOP in LPL C Buske et al 161 Kreuser, Krankenhaus Barmherzige Bru¨der, Regensburg; Daus, 15 Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster Jacobs, Schmits, Praxis, Saarbru¨cken; Walter, Schmid, Marien- ML et al. Clinicopathological definition of Waldenstrom’s macro- hospital, Stuttgart; Mergenthaler, Schleicher, Katharinenhospital, globulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s macroglobulinemia. Stuttgart; Heidemann, Kaesberger, Diakonieklinikum Stuttgart; Semin Oncol 2003; 30: 110–115. Clemens, Mutterhaus der Borromaërinnen, Trier; Diers, Twiessel, 16 Weber D, Treon SP, Emmanouilides C, Branagan AR, Byrd JC, Marienhospital, Vechta; Sandmann, Becker, Kliniken St Antonius, Blade J et al. Uniform response criteria in Waldenstrom’s Wuppertal; Einsele, Weissinger, Reimer, Universita¨tsklinik macroglobulinemia: consensus panel recommendations from the Wu¨rzburg. Second International Workshop on Waldenstrom’s macroglobulinemia. Semin Oncol 2003; 30: 127–131. 17 Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors References JM et al. Report of an international workshop to standardize response criteria for non-Hodgkin0s lymphomas. NCI Sponsored 1 Stansfeld AG, Diebold J, Noel H, Kapanci Y, Rilke F, Kelenyi G International Working Group. J Clin Oncol 1999; 17: 1244. et al. Updated Kiel classification for lymphomas. Lancet 1988; 1: 18 Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz- 292–293. Saez R et al. Follicular lymphoma international prognostic index. 2 Treon SP, Dimopoulos M, Kyle RA. Defining Waldenstrom’s Blood 2004; 104: 1258–1265. macroglobulinemia. Semin Oncol 2003; 30: 107–109. 19 Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, 3 Treon SP, Morel P, Leblond V, Fermand JP. Report of the Third Kluin-Nelemans HC et al. A new prognostic index (MIPI) for International Workshop on Waldenstrom’s macroglobulinemia. patients with advanced stage mantle cell lymphoma. Blood 2008; Clin Lymphoma 2005; 5: 215–216. 111: 558–565. 4 Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP. 20 Dimopoulos MA, Anagnostopoulos A, Zervas C, Kyrtsonis MC, Diagnosis and management of Waldenstrom’s macroglobulinemia. Zomas A, Bourantas C et al. Predictive factors for response to J Clin Oncol 2005; 23: 1564–1577. rituximab in Waldenstrom’s macroglobulinemia. Clin Lymphoma 5 Papamichael D, Norton AJ, Foran JM, Mulatero C, Mathews J, 2005; 5: 270–272. Amess JA et al. Immunocytoma: a retrospective analysis from 21 Treon SP, Branagan A, Wasi P, Emmanouilides CA, Frankel SR, St Bartholomew’s Hospital-1972–1996. J Clin Oncol 1999; 17: Lister A et al. Combination therapy with rituximab and fludarabine 2847–2853. in Waldenstrom’s macroglobulinemia. Blood 2004; 104: 753a. 6 Garcia-Sanz R, Montoto S, Torrequebrada A, de Coca AG, Petit J, 22 Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Sureda A et al. Waldenstrom macroglobulinaemia: presenting Lin KI et al. Fludarabine, cyclophosphamide, and rituximab features and outcome in a series with 217 cases. Br J Haematol for the treatment of patients with chronic lymphocytic leukemia 2001; 115: 575–582. or indolent non-Hodgkin lymphoma. Cancer 2006; 106: 7 Dhodapkar MV, Jacobson JL, Gertz MA, Rivkin SE, Roodman GD, 2412–2420. Tuscano JM et al. Prognostic factors and response to fludarabine 23 Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Zervas K, therapy in patients with Waldenstrom macroglobulinemia: results Tsatalas C, Kokkinis G et al. Primary treatment of Waldenstrom of United States intergroup trial (Southwest Oncology Group macroglobulinemia with dexamethasone, rituximab, and cyclo- S9003). Blood 2001; 98: 41–48. phosphamide. J Clin Oncol 2007; 25: 3344–3349. 8 Leblond V, Levy V, Maloisel F, Cazin B, Fermand JP, Harousseau JL 24 Lenz G, Dreyling M, Schiegnitz E, Forstpointner R, Wandt H, et al. Multicenter, randomized comparative trial of fludarabine and Freund M et al. Myeloablative radiochemotherapy followed by the combination of cyclophosphamide-doxorubicin-prednisone in autologous stem cell transplantation in first remission prolongs 92 patients with Waldenstrom macroglobulinemia in first relapse progression-free survival in follicular lymphoma: results of a or with primary refractory disease. Blood 2001; 98: 2640–2644. prospective, randomized trial of the German Low-Grade Lympho- 9 Tamburini J, Levy V, Chaleteix C, Fermand JP, Delmer A, ma Study Group. Blood 2004; 104: 2667–2674. Stalniewicz L et al. Fludarabine plus cyclophosphamide in 25 Chen CI. Treatment for Waldenstrom’s macroglobulinemia. Waldenstrom’s macroglobulinemia: results in 49 patients. Ann Oncol 2004; 15: 550–558. Leukemia 2005; 19: 1831–1834. 26 Rohatiner AZ, Gregory WM, Peterson B, Borden E, 10 Treon SP, Emmanouilides C, Kimby E, Kelliher A, Preffer F, Solal-Celigny P, Hagenbeek A et al. Meta-analysis to evaluate Branagan AR et al. Extended rituximab therapy in Waldenstrom’s the role of interferon in follicular lymphoma. J Clin Oncol 2005; macroglobulinemia. Ann Oncol 2005; 16: 132–138. 23: 2215–2223. 11 Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, 27 Ozer H, Wiernik PH, Giles F, Tendler C. Recombinant interferon- Schmits R et al. Frontline therapy with rituximab added to the alpha therapy in patients with follicular lymphoma. Cancer 1998; combination of cyclophosphamide, doxorubicin, vincristine, and 82: 1821–1830. prednisone (CHOP) significantly improves the outcome for 28 Hiddemann W, Griesinger F, Unterhalt M. Interferon alfa for patients with advanced-stage follicular lymphoma compared with the treatment of follicular lymphomas. Cancer J Sci Am 1998; 4 therapy with CHOP alone: results of a prospective randomized (Suppl 2): S13–S18. study of the German Low-Grade Lymphoma Study Group. Blood 29 van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne 2005; 106: 3725–3732. RD et al. Rituximab maintenance improves clinical outcome of 12 Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J relapsed/resistant follicular non-Hodgkin lymphoma in patients et al. CVP chemotherapy plus rituximab compared with CVP as both with and without rituximab during induction: results of a first-line treatment for advanced follicular lymphoma. Blood 2005; prospective randomized phase 3 intergroup trial. Blood 2006; 108: 105: 1417–1423. 3295–3301. 13 Buske C, Weigert O, Dreyling M, Unterhalt M, Hiddemann W. 30 Forstpointner R, Unterhalt M, Dreyling M, Bock HP, Repp R, Current status and perspective of antibody therapy in follicular Wandt H et al. Maintenance therapy with rituximab leads to a lymphoma. Haematologica 2006; 91: 104–112. significant prolongation of response duration after salvage therapy 14 Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B with a combination of rituximab, fludarabine, cyclophosphamide, et al. Immunochemotherapy with rituximab and cyclophospha- and mitoxantrone (R-FCM) in patients with recurring and refractory mide, doxorubicin, vincristine, and prednisone significantly follicular and mantle cell lymphomas: Results of a prospective improves response and time to treatment failure, but not long- randomized study of the German Low Grade Lymphoma Study term outcome in patients with previously untreated mantle cell Group (GLSG). Blood 2006; 108: 4003–4008. lymphoma: results of a prospective randomized trial of the German 31 Rothwell PM. Treating individuals 2. Subgroup analysis in Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005; randomised controlled trials: importance, indications, and inter- 23: 1984–1992. pretation. Lancet 2005; 365: 176–186.

Leukemia