VOLUME 25 䡠 NUMBER 15 䡠 MAY 20 2007

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Rituximab Added to First-Line Mitoxantrone,

Chlorambucil, and Prednisolone Chemotherapy Followed
From the HELIOS Klinikum Erfurt
by Interferon Maintenance Prolongs Survival in Patients
GmbH, Erfurt; Klinikum Ernst von
Bergmann, Potsdam; Charité, Rudolph-
With Advanced Follicular Lymphoma: An East German
Virchow-Klinikum; Charité, Campus
Klinikum Benjamin Franklin, Berlin; Klini-
Study Group Hematology and Oncology Study
kum Chemnitz, Chemnitz; Klinikum der Michael Herold, Antje Haas, Stefanie Srock, Sabine Neser, Kathrin Haifa Al-Ali, Andreas Neubauer,
Universität Leipzig, Leipzig; Klinikum Gottfried Dölken, Ralph Naumann, Wolfgang Knauf, Mathias Freund, Robert Rohrberg, Klaus Höffken,
der Philips Universität Marburg,
Astrid Franke, Thomas Ittel, Erika Kettner, Ursula Haak, Ulrich Mey, Christian Klinkenstein,
Marburg; Klinikum der Ernst-Moritz-
Michael A␤mann, and Ullrich von Grünhagen
Arndt Universität, Greifswald; Klinikum
der Technischen Universität Dresden,
A B S T R A C T
Dresden; Onkologische Schwerpunkt-
praxis Frankfurt/Main, Frankfurt/Main;
Klinikum der Universität Rostock, Purpose
Rostock; Onkologische Schwerpunkt- Rituximab has been shown to be active in follicular lymphoma (FL), both as monotherapy and in
praxis; Städitisches Krankenhaus combination with chemotherapy. We conducted a randomized trial comparing mitoxantrone,
Martha-Maria Halle-Dölau, Halle; Klini- chlorambucil, and prednisolone (MCP) chemotherapy plus rituximab with MCP alone.
kum der Friedrich-Schiller-Universität,
Jena; Klinikum der Otto-von-Guericke- Patients and Methods
Universität; Städtisches Klinikum Previously untreated patients with stage III or IV CD20⫹ indolent or mantle cell lymphoma were
Magdeburg, Magdeburg; Klinikum der randomly assigned to either eight 28-day cycles of MCP plus rituximab (R-MCP; n ⫽ 181) or eight
Hansestadt Stralsund GmbH, Stralsund; cycles of MCP alone (n ⫽ 177). All patients who achieved a complete or partial remission were
Klinikum der Rheinischen Friedrich-
treated with interferon maintenance until relapse. Herein, we report the results from the primary
Wilhelms Universität Bonn, Bonn; Klini-
kum Frankfurt/Oder, Frankfurt;
analysis population of patients with FL, who constituted the majority of patients (56%) recruited
Krankenhaus Riesa, Riesa; and Onkolo- to the trial (n ⫽ 201; R-MCP, n ⫽ 105; MCP, n ⫽ 96).
gische Schwerpunktpraxis, Cottbus,
Results
Germany.
Rates of overall and complete response were significantly higher in the R-MCP arm than the MCP
Submitted March 8, 2006; accepted arm (overall response, 92% v 75%, respectively; P ⫽ .0009; complete response, 50% v 25%,
February 16, 2007; published online
respectively; P ⫽ .004). With a median follow-up time of 47 months, median event-free survival
ahead of print at www.jco.org on April 9,
2007.
(EFS) and progression-free survival (PFS) times were significantly prolonged with R-MCP com-
pared with MCP (EFS, not reached v 26 months, respectively; P ⬍ .0001; PFS, not reached v 28.8
Supported by grants from F. Hoffmann–
months, respectively; P ⬍ .0001), and overall survival (OS) was significantly improved with R-MCP
La Roche Ltd, Germany.
compared with MCP (4-year OS rate, 87% v 74%, respectively; P ⫽ .0096).
Presented in part at the 46th Annual
Meeting of the American Society of Conclusion
Hematology, December 4-7, 2004, San The R-MCP regimen significantly improves complete and overall response rates, EFS, PFS,
Diego, CA; the 9th International Confer- and OS in patients with previously untreated advanced FL, without a clinically significant
ence on Malignant Lymphoma, June increase in toxicity.
8-11, 2005, Lugano, Switzerland; and
the 48th Annual Meeting of the Ameri-
can Society of Hematology, December
J Clin Oncol 25:1986-1992. © 2007 by American Society of Clinical Oncology
9-12, 2006, Orlando, FL.

Authors’ disclosures of potential con- agents alone but with no improvement in overall
INTRODUCTION
flicts of interest and author contribu-
survival (OS).4 Intensive nonmyeloablative chemo-
tions are found at the end of this
article. Patients with follicular lymphoma (FL), the most therapy can achieve clinical and molecular remis-
Address reprint requests to Michael
common form of indolent non-Hodgkin’s lym- sion but with no evidence of cure.5
Herold, MD, HELIOS Klinikum Erfurt phoma (NHL),1 have a median survival time of 6 Although the use of myeloablative chemother-
GmbH, 2 Medizinische Klinik, Bereich to 10 years and a pattern of repeated relapses, gener- apy with autologous stem-cell support has been
Hamatologie/Onkologie, Nordhauserstr
74, 99089, Erfurt, Germany; e-mail:
ally with progressively shorter periods of remission shown to confer a disease-free and OS advantage
miherold@erfurt.helios-kliniken.de. between each relapse.2,3 For patients with ad- compared with conventional chemotherapy in pa-
© 2007 by American Society of Clinical vanced FL requiring treatment, the use of combina- tients with relapsing FL,6 the value of this approach
Oncology tion chemotherapy and prolonged therapy has been in the first-line setting remains less clear. In a recent
0732-183X/07/2515-1986/$20.00 shown to improve response rates and extend first study comparing high-dose therapy followed by
DOI: 10.1200/JCO.2006.06.4618 remission compared with short-term alkylating purged autologous stem-cell transplantation with

1986
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Copyright © 2007 American Society of Clinical Oncology. All rights reserved.
 MCP Plus Rituximab in Follicular Lymphoma

cyclophosphamide, doxorubicin, vincristine, and prednisolone independent ethics committee and the local ethics committees at each
(CHOP) chemotherapy followed by interferon in patients with newly participating center. The study has been registered as East German Study
diagnosed advanced FL, the high-dose therapy group achieved higher Group Hematology and Oncology Trial 39 and at ClinicalTrials.gov (http://
www.clinicaltrials.gov/) under ID 00269113.
response rates and longer median event-free survival (EFS). However,
this did not translate into a better survival rate because of an excess of Random Assignment
secondary malignancies.7 Eligible patients were assigned at trial entry to treatment with either MCP
The chimeric monoclonal antibody rituximab binds avidly to the or R-MCP. Random assignment was performed centrally using a randomiza-
tion list, with patients stratified according to histologic status.
CD20 antigen, which is expressed on almost all malignant B cells.8
Patients with heavily pretreated indolent NHL receiving rituximab Treatment
monotherapy achieved an overall response rate (ORR) of 48% with Patients randomly assigned to treatment with MCP received a combina-
tion of mitoxantrone 8 mg/m2 intravenously (IV) on days 1 and 2; chloram-
low levels of toxicity.9 Rituximab can sensitize NHL cells to a range of
bucil 3 ⫻ 3 mg/m2 orally (PO) on days 1 to 5; and prednisolone 25 mg/m2 PO
chemotherapeutic agents.10,11 For instance, in the first ever study on days 1 to 5. Patients treated with R-MCP received rituximab 375 mg/m2 IV
combining rituximab with CHOP, the ORR in patients with indolent on day 1 of each therapy cycle, followed by mitoxantrone (8 mg/m2 IV) on
NHL was 100%, and this translated into excellent long-term out- days 3 and 4, chlorambucil (3 ⫻ 3 mg/m2 PO) on days 3 to 7, and prednisolone
comes, with a median time to progression of 82.3 months.12,13 In a (25 mg/m2 PO) on days 3 to 7.
recently published phase III study of rituximab plus CHOP versus If a grade 3 or 4 rituximab-induced infusion reaction occurred, therapy
CHOP alone in FL patients, the addition of rituximab to CHOP was interrupted. All symptoms had to resolve or decrease in severity to grade 1
before rituximab was continued or MCP was started.
significantly improved ORR compared with CHOP alone (96% v Patients were treated every 28 days for a maximum of eight cycles.
90%, respectively; P ⫽ .011), and after a median follow-up time of MCP dosages were reduced by 25% for mitoxantrone and chlorambucil if
18 months, the risk of treatment failure was significantly reduced severe myelosuppression occurred (leukocyte and/or platelet levels reduced to
(P ⬍ .0001). Estimated 2-year survival rates were 95% for rituximab ⬍ 1.0 ⫻ 109/L and ⬍ 75 ⫻ 109/L, respectively).
plus CHOP and 90% for CHOP alone (P ⫽ .016).14 Maintenance therapy with interferon alfa-2a (4.5 MU three times per
The combination of mitoxantrone, chlorambucil, and pred- week until relapse) was planned in all study patients with FL who had achieved
partial remission (PR) or complete remission (CR) and was initiated within 4
nisolone (MCP) has been shown to be effective and well tolerated in
to 8 weeks after treatment completion. After completion of induction treat-
patients with indolent NHL.15,16 Because rituximab can enhance the ment, patients were observed every 8 weeks during the first year, at 3-month
cytotoxicity of both mitoxantrone and glucocorticosteroids in intervals during the second year, and then every 6 months from the third year
vitro17,18 and has no overlapping toxicities, the addition of rituximab onward.
to MCP chemotherapy might be expected to enhance the efficacy of
Response to Treatment and Adverse Events
this regimen without significantly increasing toxicity. For these rea- The primary end point was remission rate, which was defined as the rate
sons, we initiated a multicenter, randomized phase III trial comparing of CR and PR after induction therapy. CR required complete resolution of all
the efficacy and toxicity of the standard MCP chemotherapeutic reg- disease symptoms, including lymph node swellings, hepatomegaly, and
imen with the combination of rituximab and MCP (R-MCP) in pa- splenomegaly recorded at study entry and normalization of blood counts for a
tients with previously untreated indolent NHL and mantle cell minimum of 4 weeks. In patients with initial lymphoma infiltration of the
lymphoma (MCL). bone marrow, CR had to be confirmed by bone marrow biopsy. Any uncon-
firmed CRs were classified as PRs. PR was defined as ⱖ 50% decrease of all
measurable/assessable lymphoma manifestations and normalization of blood
PATIENTS AND METHODS counts for a minimum of 4 weeks, without occurrence of new lymphoma
manifestations. Progressive disease (PD) was defined as an increase in tumor
burden or splenomegaly by 25% or more or the appearance of new tumor
Patients lesions. Patients were classified as having no change if they did not have CR,
Patients were eligible for inclusion onto the study if they were aged PR, or PD.
between 18 and 75 years and had untreated, histologically confirmed, CD20⫹ Secondary efficacy parameters included progression-free survival (PFS;
indolent NHL (FL, grade 1 and 2 only; lymphoplasmacytic lymphoma) and interval from random assignment date to progression of disease or death from
MCL. All patients were required to have stage III or IV disease according to the NHL), OS (interval from random assignment date to death from any cause),
Ann Arbor classification and a general performance status of ⱕ 2 according to and toxicity (graded in accordance with the National Cancer Institute of
the Eastern Cooperative Oncology Group scale. Canada Common Toxicity Criteria grading system).19 Other efficacy param-
Patients were required to be in need of therapy defined by the presence of eters assessed included EFS (interval from random assignment date to treat-
at least one of the following criteria: “B” symptoms or extranodal manifesta- ment failure, which was defined as PD after two cycles and failure to achieve at
tion; hematopoietic insufficiency (hemoglobin ⬍ 10 g/dL and/or platelets least PR at cycle 6, disease progression, relapse, or death from any cause),
⬍ 100,000/␮L); rapid tumor growth (doubling of the product of the end-to- duration of response (interval from first assessment of CR or PR to disease
end diameters of the measurable lymphoma manifestation within 6 months); progression), and time to next antilymphoma treatment (interval from ran-
bulky disease (lymphoma ⬎ 7.5 cm in diameter; mediastinal tumor ⬎ one dom assignment date to the time when new treatment was initiated).
third of thorax diameter at thoracic vertebra 5/6); or immunohematologic Tumor responses were assessed after two treatment cycles, after six treat-
phenomena (eg, hemolytic anemia or immune thrombocytopenia). Patients ment cycles, and 4 weeks after completion of study treatment. Response
with concomitant diseases and/or restricted organ function not caused by assessment included all diagnostic measures used in the pretherapeutic staging
lymphoma or patients with HIV infection were excluded from the study. (including computed tomography scans of neck, chest, abdomen, and pelvis
The histologic diagnosis had to be centrally confirmed by a designated refer- and bone marrow biopsy). Patients with disease progression after two cycles of
ence pathologist. therapy were prematurely withdrawn from study treatment and were consid-
The study complied with all of the requirements of the Declaration of ered as having treatment failure in the analysis of EFS. Patients who had not
Helsinki and its current amendments and was conducted in accordance reached a PR or CR after six cycles of therapy were also classified as experienc-
with good clinical practice guidelines. All patients gave written informed ing treatment failure in the EFS analysis. Patients with a CR or a PR after six
consent. The protocol and accompanying materials were approved by an cycles of chemotherapy or immunochemotherapy, respectively, received a

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Copyright © 2007 American Society of Clinical Oncology. All rights reserved.
 Herold et al

further two consolidation cycles of MCP or R-MCP for a total of eight treat-
ment cycles. Patients screened
N = 376
Statistical Analysis
The primary end point of the trial according to the protocol was ORR Screening failure
(CR ⫹ PR). Although the protocol allowed the inclusion of patients with FL, n=0

lymphoplasmacytic lymphoma, and MCL, the primary analysis population Patients randomly
assigned
was defined as the population of FL patients. Efficacy analyses for patients with n = 376
MCL and lymphoplasmacytic lymphoma were preplanned as exploratory Patients not receiving
analyses. Although the primary end point was response rate, the study sample study drug
size was calculated using the end point of PFS after 4 years. In patients with FL, n = 16
No CRF data available (2)
a 4-year PFS rate of 45% was assumed for patients after treatment with MCP. Protocoal deviation (9)
It was calculated that 216 patients with FL, randomly assigned in a ratio of 1:1 Consent withdrawn (3)*
between the study arms, would provide 80% power at a two-tailed significance Death during study (1)
Lost to follow-up (1)*
level of 5% to detect an anticipated increase in the 4-year PFS rate by 20% to Other reason (1)
65% after treatment with R-MCP. Two preplanned interim analyses were Patients receiving
study drug
conducted; the first analysis was conducted after 50 patients were randomly (safety population)
assigned, and the second analysis was conducted after 124 patients were ran- n = 360
domly assigned; a predefined P value of .0001 was used for each interim
analysis. The main efficacy analysis of the primary end point of remission rate
was planned after all randomly assigned patients completed induction therapy.
Because the primary end point of the study was reached in the main analysis,
Treatment arm A Treatment arm B
one updated analysis with longer follow-up (47 months) on time-dependent (MCP) (rituximab + MCP)
parameters (PFS, EFS, OS, and others) was conducted. A final analysis is n = 177 n = 183
planned after all patients have completed a follow-up period of 4 years.
Statistical analysis of the difference in remission rates between treatment
groups was undertaken using a two-sided Fisher test with ␣ ⫽ .05 (null Completed Withdrawn Completed Withdrawn
hypothesis: remission rate for R-MCP was equal to that for MCP alone; n = 103 n = 74 n = 146 n = 37
alternative hypothesis: there was a statistically significant difference in remis-
sion rates between the two treatment arms). PFS and OS after 4 years of
Fig 1. CONSORT diagram: overall study population. *One patient withdrew his
follow-up were to be analyzed by the log-rank test (␣ ⫽ .05) with results consent and was lost to follow-up as well. †Suicide before starting treatment.
expressed as Kaplan-Meier plots. The Mantel-Haenszel ␹2 test (␣ ⫽ .05) was Two patients started treatment with rituximab plus MCP but did not receive at
used to compare differences in toxicity between treatment groups. Analyses of least one complete therapy cycle. Therefore, the intent-to-treat population
efficacy and safety included all randomly assigned and treated patients with FL encompassed 358 patients (177 patients in the MCP group and 181 patients in
and followed the intent-to-treat principle (ie, all patients included were ana- the rituximab plus MCP group). Withdrawn means did not respond to treatment
with complete or partial remission. CRF, case report form; MCP, mitoxantrone,
lyzed according to their randomly assigned treatment). Statistical analyses
chlorambucil, and prednisolone.
were performed using SAS software (SAS Institute, Cary, NC). Patients will
continue to be observed to obtain progression and survival information up to
4 years after the last patient has completed the last treatment cycle.
curred in three R-MCP patients and 10 MCP patients, and failure to
achieve at least PR after six cycles occurred in seven R-MCP patients
RESULTS and 22 MCP patients. Mean doses of study drug administered were as
follows: rituximab, 660 to 680 mg/cycle; mitoxantrone, 24 to 28 mg/
This open-label study was conducted at 34 active centers in Germany. cycle; chlorambucil, 68 to 81 mg/cycle; and prednisolone, 226 to 231
A total of 358 patients were randomly assigned (177 patients assigned mg/cycle. Dose-intensity of the chemotherapy did not differ between
to MCP and 181 patients assigned to R-MCP) on the study between treatment arms. Interferon alfa maintenance treatment (3 ⫻ 4.5 MU
October 1998 and September 2003. The primary analysis population per week until disease progression) was initiated in 97% and 92% of
consisted of a total of 201 patients with confirmed FL (MCP, n ⫽ 96; planned patients in the R-MCP group and MCP group, respectively.
R-MCP, n ⫽ 105; Figs 1 and 2). To date, the median duration of interferon maintenance treatment is
15.5 months in the R-MCP group and 9.5 months in the MCP group,
Baseline Characteristics with the difference being a result of earlier disease progression in the
Baseline demographic, clinical, and pathologic characteristics of MCP group.
the FL population were well balanced across treatment groups with
the exception of sex (Table 1). The Follicular Lymphoma Interna- Efficacy
tional Prognostic Index was applied retrospectively, and the vast ma- Investigators assessed remission rates (CR and PR) according to
jority of patients (94% in the MCP group and 92% in the R-MCP the criteria outlined in the study protocol. At the end of therapy, 92%
group) had intermediate- or high-risk disease according to the index. of the FL patients treated with R-MCP were in remission (50% CR
rate) compared with 75% of patients in the MCP arm (25% CR rate).
Treatment Both overall remission and CR rates for R-MCP were significantly
All eight cycles of therapy were administered to 88% of the FL superior to those for MCP (P ⫽ .0009 and P ⫽ .0004, respectively;
population receiving R-MCP and 67% of the FL population receiving Table 2).
MCP. This difference was mainly a result of fewer premature with- Median follow-up time for FL patients is now 47 months (R-
drawals from study treatment as a result of treatment failure in the MCP, 49 months; MCP, 42 months). In the PFS analysis, 30 events
R-MCP arm; treatment failures caused by PD after two cycles oc- have occurred in the R-MCP group, and 50 events have occurred in

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 MCP Plus Rituximab in Follicular Lymphoma

Table 1. Baseline Characteristics of the Intent-to-Treat Population

Follicular lymphoma patients (N = 201) of Patients With Follicular Lymphoma
R-MCP
MCP n = 96 R-MCP n = 105 MCP (n ⫽ 96) (n ⫽ 105)
No. of No. of
2 cycles Characteristic Patients %ⴱ Patients %ⴱ
Age, years
Median 57 60
86 CR, PR, NC, 102
Range 31-75 33-78
10 PD 3 Sex, male 36 37 53 50
Ann Arbor stage
III 22 23 30 29
4 cycles
IV 74 77 75 71
ECOG performance status
74 CR, PR 98 0 54 56 68 65
1 36 38 29 28
22 < PR 7
2 6 6 7 7
LDH ⬎ normal 30 31 31 30
2 cycles Bone marrow infiltration 71 74 73 70
B symptoms
Nightly sweating 34 35 46 44
72 CR, PR 97 Fever ⬎ 38°C 2 2 4 4
24 < PR 8 Body weight loss† 20 21 16 15
Follicular Lymphoma International
Prognostic Index scores
Fig 2. Outcome according to treatment group and cycle of treatment in patients
with follicular lymphoma. MCP, mitoxantrone, chlorambucil, and prednisolone; Low 6 6 8 8
R-MCP, rituximab plus mitoxantrone, chlorambucil, and prednisoline; CR, com- Intermediate 37 39 38 36
plete remission, PR, partial remission, NC, no change; PD, progressive disease. High 53 55 59 56

Abbreviations: MCP, mitoxantrone, chlorambucil, and prednisolone; R-MCP,

rituximab plus mitoxantrone, chlorambucil, and prednisolone; ECOG, Eastern
Cooperative Oncology Group; LDH, lactate dehydrogenase.
the MCP group. The administration of R-MCP significantly pro- ⴱ
Percentages based on the intent-to-treat population.
longed PFS compared with MCP (median PFS, not reached v 28.8 †Loss of ⬎ 10% body weight within 6 months.
months, respectively; P ⬍ .0001; Fig 3; Table 2). In the analysis of EFS,
34 patients in the R-MCP group and 57 patients in the MCP group
have experienced a treatment failure event. Treatment with R-MCP
significantly lengthened EFS compared with treatment with MCP rates and a doubling of the CR rate compared with MCP chemother-
(median EFS, not reached v 26 months, respectively; P ⬍ .0001; Table apy alone. This is particularly impressive since unconfirmed CR20 was
2). In the analysis of OS, there have been 15 deaths in the R-MCP arm regarded as PR only. After a median follow-up period of 47 months,
and 25 deaths in the MCP arm. Median OS time has not been reached this excellent remission rate translated into significantly improved
in either treatment group, with 4-year OS rates being 87% for R-MCP
and 74% for MCP (P ⫽ .0096; Fig 4; Table 2). During the study period
and follow-up, there were 24 cause-specific deaths in the FL patient Table 2. Results of an Intent-to-Treat Analysis of End Points for
population (seven in the R-MCP arm and 17 in the MCP arm; Patients With Follicular Lymphoma
P ⫽ .0159). MCP R-MCP
End Point (n ⫽ 96) (n ⫽ 105) P
Adverse Events Tumor responses
Adverse events were reported more frequently in the R-MCP arm Complete remission .0004
than in the MCP arm (99% v 86% of patients, respectively). As ex- No. of patients 24 52
pected, the most common adverse events observed were related to the %ⴱ 25 50
blood and bone marrow (Table 3). Seventy-two percent of patients in Complete plus partial remission .0009
No. of patients 72 97
the R-MCP group versus 58% of patients in the MCP group experi- %ⴱ 75 92
enced grade 3 or 4 leukopenia. Infections of grade 3 or 4 were observed Median progression-free survival 28.8 NR ⬍ .0001
in 8% of the MCP group and 7% of the R-MCP group. No cases of time, months
secondary myelodysplastic syndrome (MDS) or acute myeloid leuke- 4-year overall survival rate, % 74 87 .0096
Median event-free survival time, 26 NR ⬍ .0001
mia (AML) have been recorded so far. months
Median response duration, months 35 NR ⬍ .0001
Median time to next treatment, 29.4 NR .0002
DISCUSSION months

Abbreviations: MCP, mitoxantrone, chlorambucil, and prednisolone; R-MCP,

rituximab plus mitoxantrone, chlorambucil, and prednisolone; NR, not
The results of this randomized trial demonstrate that the addition of reached.
ⴱ
rituximab to the MCP chemotherapy regimen in patients with previ- Percentages based on the intent-to-treat population.
ously untreated FL leads to highly significantly improved remission

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Copyright © 2007 American Society of Clinical Oncology. All rights reserved.
 Herold et al

1.00 1.00
Survival Distribution

Survival Distribution
0.75 0.75
Function

Function
0.50 0.50

0.25 R-MCP: median not reached 4-year PFS 71% 0.25 R-MCP: median not reached 4-year OS 87%
MCP: median 28.8 months 4-year PFS 40% MCP: median not reached 4-year OS 74%
P < .0001 P = .0096

0 10 20 30 40 50 60 0 10 20 30 40 50 60

PFS (months) OS (months)

Fig 3. Progression-free survival (PFS) time for 201 follicular lymphoma patients Fig 4. Overall survival (OS) time for 201 follicular lymphoma patients assigned
assigned to chemotherapy with either mitoxantrone, chlorambucil, and pred- to chemotherapy with either mitoxantrone, chlorambucil, and prednisolone
nisolone (MCP) or MCP plus rituximab (R-MCP). (MCP) or MCP plus rituximab (R-MCP).

time to event variables for patients receiving R-MCP. Most impor- event-free interval with less nonhematologic toxicity compared with
tant, the OS of patients treated with R-MCP chemotherapy was cyclophosphamide, vincristine, and prednisone chemotherapy.25
significantly prolonged (4-year OS rate, 87% for R-MCP v 74% for Subsequent trials in indolent NHL have shown MCP to be an effective,
MCP; median OS time, not yet reached in both groups; P ⫽ .0096). well-tolerated regimen.15,16 We have shown here that the addition of
R-MCP is a well-tolerated regimen, with a pattern of adverse rituximab to this regimen significantly improves the survival of pa-
events similar to that seen with MCP alone. Although more patients tients with previously untreated FL, with no clinically significant in-
receiving R-MCP had grade 3 or 4 leukopenia compared with patients crease in toxicity.
treated with MCP, this did not translate into an increased rate of The addition of rituximab to other chemotherapy regimens has
infections. To date, no patients in either treatment group have devel- also been shown to improve clinical outcome without increasing tox-
oped treatment-related MDS or AML. However, patients must be icity. In a recent trial comparing eight cycles of cyclophosphamide,
carefully observed because treatment with alkylating agents such as vincristine, and prednisone (CVP) chemotherapy with rituximab plus
chlorambucil is known to increase the risk of MDS or AML,21 and CVP as first-line treatment for patients with FL, patients receiving
mitoxantrone may augment this effect.22 rituximab plus CVP achieved highly significantly improved response
The combination of prednimustine, an ester of chlorambucil and rates, time to treatment failure, time to progression, and OS compared
prednisolone, and mitoxantrone was first introduced into NHL ther- with patients receiving CVP (4-year OS rate, 83% v 77%, respectively;
apy in the 1980s.23,24 A subsequent randomized trial in patients with P ⫽ .029).26,27
indolent NHL and MCL demonstrated that prednimustine plus mi- The addition of rituximab has also been shown to significantly
toxantrone treatment resulted in a significantly higher CR rate and improve response rates and long-term outcomes for patients receiving

Table 3. Adverse Events According to NCIC-CTC Grading System Occurring in ⱖ 10% of Follicular Lymphoma Patients Treated With MCP or R-MCP:
Intent-to-Treat Analysis
MCP R-MCP
(n ⫽ 96) (n ⫽ 105)
Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4
Adverse No. of No. of No. of No. of No. of No. of No. of No. of
Event Patients % Patients % Patients % Patients % Patients % Patients % Patients % Patients %
WBC 3 3 5 5 21 22 35 36 0 0 3 3 25 24 50 48
Infection 12 12 22 23 7 7 1 1 20 19 24 23 6 6 1 1
Platelets 13 14 19 20 6 6 1 1 11 10 20 19 4 4 0 0
Nausea 9 9 5 5 6 6 0 0 20 19 5 5 1 1 0 0
Hemoglobin 11 12 7 7 3 3 1 1 10 10 8 8 2 2 1 1
Rash 0 0 1 1 2 2 0 0 7 7 9 9 0 0 0 0
Heartburn 2 2 1 1 0 0 0 0 5 5 10 10 1 1 0 0
Insomnia 4 4 3 3 0 0 0 0 12 11 3 3 0 0 0 0
Diarrhea 3 3 1 1 0 0 2 2 7 7 4 4 2 2 0 0
Stomatitis 2 2 5 5 1 1 0 0 7 7 4 4 1 1 0 0
Bone pain 5 5 5 5 0 0 0 0 4 4 6 6 2 2 0 0
GI 1 1 4 4 1 1 1 1 5 5 4 4 2 2 0 0
Other 4 4 4 4 1 1 1 1 7 7 4 4 0 0 0 0

Abbreviations: NCIC-CTC, National Cancer Institute of Canada Common Toxicity Criteria; MCP, mitoxantrone, chlorambucil, and prednisolone; R-MCP, rituximab
plus mitoxantrone, chlorambucil, and prednisolone.
*
Number of patients reporting each event.

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Copyright © 2007 American Society of Clinical Oncology. All rights reserved.
 MCP Plus Rituximab in Follicular Lymphoma

six to eight cycles of CHOP (as described earlier)14 or six cycles of Naumann, Roche, Germany; Robert Rohrberg, Roche, Germany
cyclophosphamide, doxorubicin, etoposide, and prednisone plus Research Funds: Michael Herold, Roche, Germany; Stefanie Srock,
interferon alfa as first-line treatment for FL.28 It is interesting to note Roche, Germany; Andreas Neubauer, Roche, Germany, Novartis,
Germany, Medac Schering, Germany; Gottfried Dölken, Roche,
that combining rituximab with cyclophosphamide, doxorubicin, Germany Testimony: N/A Other: N/A
etoposide, and prednisone and interferon alfa led to high rates of
complete response (complete response/unconfirmed complete re-
sponse rate at 6 months, 76% with rituximab v 49% in the control AUTHOR CONTRIBUTIONS
arm; P ⬍ .0001). It is possible that rituximab and interferon have a
synergistic effect, leading to improvements in the quality and du- Conception and design: Michael Herold, Gottfried Dölken, Mathias
Freund, Astrid Franke
ration of response when the two biologic agents are used together
Provision of study materials or patients: Michael Herold, Antje Haas,
with chemotherapy. Maintenance therapy with interferon14,29 or Stefanie Srock, Sabine Neser, Kathrin Haifa Al-Ali, Andreas Neubauer,
rituximab30-33 after successful induction may prolong duration of Gottfried Dölken, Ralph Naumann, Wolfgang Knauf, Mathias Freund,
response both in previously untreated or relapsed FL patients. The Robert Rohrberg, Klaus Höffken, Astrid Franke, Thomas Ittel, Erika
R-MCP regimen should become a new standard treatment for all Kettner, Ursula Haak, Ulrich Mey, Christian Klinkenstein, Michael
patients with previously untreated advanced FL requiring thera- A␤mann, Ullrich von Grünhagen
peutic intervention. Collection and assembly of data: Michael Herold, Antje Haas, Stefanie
Srock, Sabine Neser, Kathrin Haifa Al-Ali, Andreas Neubauer, Gottfried
Dölken, Ralph Naumann, Wolfgang Knauf, Mathias Freund, Robert
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS Rohrberg, Klaus Höffken, Astrid Franke, Thomas Ittel, Erika Kettner,
OF INTEREST Ursula Haak, Ulrich Mey, Christian Klinkenstein, Michael A␤mann,
Ullrich von Grünhagen
Although all authors completed the disclosure declaration, the following Data analysis and interpretation: Michael Herold, Kathrin Haifa Al-Ali,
authors or their immediate family members indicated a financial interest. Andreas Neubauer
No conflict exists for drugs or devices used in a study if they are not being Manuscript writing: Michael Herold, Kathrin Haifa Al-Ali, Andreas
evaluated as part of the investigation. For a detailed description of the Neubauer, Gottfried Dölken
disclosure categories, or for more information about ASCO’s conflict of Final approval of manuscript: Michael Herold, Antje Haas, Stefanie
interest policy, please refer to the Author Disclosure Declaration and the Srock, Sabine Neser, Kathrin Haifa Al-Ali, Andreas Neubauer, Gottfried
Disclosures of Potential Conflicts of Interest section in Information Dölken, Ralph Naumann, Wolfgang Knauf, Mathias Freund, Robert
for Contributors. Rohrberg, Klaus Höffken, Astrid Franke, Thomas Ittel, Erika Kettner,
Employment: N/A Leadership: N/A Consultant: Michael Herold, Ursula Haak, Ulrich Mey, Christian Klinkenstein, Michael A␤mann,
Roche, Germany Stock: N/A Honoraria: Michael Herold, Roche; Ullrich von Grünhagen
Andreas Neubauer, Roche, Germany, Novartis, Germany; Ralph Other: Michael Herold [Principle investigator of the respective clinical trial]

8. Reff ME, Carner K, Chambers KS, et al: De- sults of a prospective randomized study of the
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