Leukemia & Lymphoma, October 2014; 55(10): 2384–2386 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.871280
Letter to the Editor
Usefulness of second rituximab maintenance after relapse in patients with follicular and mantle cell lymphoma Blanca Sanchez-Gonzalez, Eva Gimeno, Francesc Garcia-Pallarols, Agueda Ancochea & Antonio Salar Department of Hematology, Hospital del Mar – IMIM, Barcelona, Spain
Rituximab–chemotherapy induction followed by maintenance therapy with rituximab is the standard front-line treatment for follicular lymphoma (FL) [1] and older patients with mantle-cell lymphoma (MCL) [2]. Currently, many patients have previously received maintenance rituximab when they relapse [3,4]. In this setting, the usefulness of a second maintenance with rituximab is unknown. We identified 10 patients with FL and three with MCL from our lymphoma registry. All patients with FL or MCL who received a second maintenance with rituximab were included in this study (Table I). All but three cases started first rituximab maintenance (RM1) in complete remission (CR) after immunotherapy or immunochemotherapy. When relapse or progression occurred, eight patients fulfilled the criteria for rituximab refractoriness. Nevertheless, all but one received rituximab-containing therapy as subsequent treatment. RM1 schedules were: 375 mg/m2/week for 4 weeks every 6 months or 375 mg/m2 every 3 months, both for 2 years or until progression. The second rituximab maintenance (RM2) schedule was: 375 mg/m2 every 3 months for 2 years or until progression. Nine patients achieved CR and four patients achieved a partial remission (PR), and then RM2 was started. While all patients who started RM2 in PR progressed during maintenance (median time to progression was 5 months), only three patients (33%) who entered RM2 in CR progressed (median time to progression was not reached; p 0.00566) (Figure 1). Interestingly, the median duration of response after RM2 was longer than after RM1 (30 vs. 18 months, respectively; p 0.656). RM2 was well tolerated with similar toxicities in comparison with RM1. No toxicities leading to RM2 discontinuation were noted. Current management of some B-cell lymphomas includes rituximab-containing chemotherapy followed by rituximab maintenance. There are no established recommendations about the role of RM2 for relapsed patients who have previously received rituximab maintenance and,
at present, this clinical situation is increasing strikingly. Within the limits of this small retrospective analysis, our results suggest that RM2 has encouraging clinical activity in those patients starting the procedure in CR according to International Working Group (IWG) response criteria [5]. RM2 is well tolerated with only minor toxicity. In addition, our findings suggest that current criteria regarding rituximab refractoriness should also be revisited, since most patients fulfilling these criteria responded to rituximabbased therapy. In conclusion, RM2 is feasible, effective and safe, and has promising activity in particular in patients starting the procedure in CR. However, prospective studies should confirm our data.
Figure 1. Time to progression from starting second rituximab maintenance to next progression or last follow-up. Kaplan–Meier curves and significance according to log-rank test. CR, complete remission; PR, partial remission.
Correspondence: Blanca Sanchez-Gonzalez, MD, PhD, Department of Hematology, Hospital del Mar, Barcelona, Spain. Tel/fax: 34-93-248-3343. E-mail: [email protected] Received 4 October 2013; accepted 24 November 2013
2384
65
53
70
3 M FL grade 2
4 M FL grade 2
5 F
72
FL grade 3A
FL grade 1
FL grade 3A
7 F
8 F
9 F
MCL
12 F
62
IV
IV
IV
IV
IV
II
IV
IV
II
III
IV
II
I
2
3
4
3
4
1
3
2
2
1
2
1
1
IPI
Treatment
R-CVP
R-CVP
R-CHOP
R-EPOCH
R-CMyOP
1st line
CVP
2nd line R-FCM
1st line
1st line
2nd line R-CMyOP
1st line
1st line
1st line
2nd line Rituximab monotherapy 3rd line Rituximab monotherapy 1st line Rituximab monotherapy 2nd line Rituximab monotherapy 1st line Chlorambucil
Line of treatment
CR
CR
CR
PR
CR
PR
CR
CR
CR
PR
CR
CR
CR
4 weeks every 6 months 4 weeks every 6 months 4 weeks every 6 months 4 weeks every 6 months 4 weeks every 6 months 1 week every 3 months 4 weeks every 6 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 4 weeks every 6 months 1 every 3 months 4 weeks every 6 months 93
20
55
25
22
13
10
11
19
12
50
82
50
70
72
75
84
86
74
74
67
73
54
71
74
85
IV
I
IV
IV
IV
II
IV
II
III
IV
IV
I
III
Age (years) Stage
2
1
2
2
2
2
2
1
3
1
3
1
2
Treatment
2nd line Rituximab monotherapy
4th line R-GEMOX
2nd line R-FCM
2nd line bendamustine
4th line R-bendamustine
2nd line R-bendamustine
2nd line R-EPOCH
2nd line R-FC
2nd line R-chlorambucil
3rd line R-CHOP
4th line Rituximab monotherapy 4th line Rituximab monotherapy 2nd line R-CVP
Line of IPI treatment
CR
CR
CR
PR
CR
PR
CR
CR
CR
CR
PR
CR
PR
1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months
10
45
33
3
28
11
30
36
62
5
8
32
5
No
No
No
Yes
Yes
Yes
Yes
No
No
Yes
Yes
No
Yes
Duration of response Rituximab at last maintenance follow-up Response schedule (months) Relapse
Second rituximab maintenance
liposomal adriamycin, vincristine and prednisone; R-EPOCH, rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine and prednisone; R-FCM, rituximab, fludarabine, cyclophosphamide and mitoxantrone; R-FC, rituximab, fludarabine and cyclophosphamide; R-CVP, rituximab, cyclophosphamide, vincristine and prednisone; CVP, cyclophosphamide, vincristine and prednisone; R-GEMOX, rituximab, gemcitabine and oxaliplatin, R-, chlorambucil, rituximab, chlorambucil; PR, partial remission, CR, complete remission.
FL, follicular lymphoma; MCL, mantle cell lymphoma; M, male; F, female; IPI, International Prognostic Index; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-CMyOP, rituximab, cyclophosphamide,
13 M FL grade 1
70
MCL
11 F
66
81
10 M MCL
83
73
65
6 M FL grade 3A
FL grade 1
67
FL grade 2
2 F
78
FL grade 1
Age (years) Stage
1 F
ID Sex Histology
Duration Rituximab of maintenance response Response schedule (months)
First rituximab maintenance
Table I. Patient characteristics, treatments and responses during first and second rituximab maintenance.
Letter to the Editor 2385
2386 B. S. Gonzalez et al. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011;377:42–51.
[2] Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med 2012;367: 520–531. [3] van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010;28:2853–2858. [4] Hainsworth JD, Litchy S, Burris HA 3rd, et al. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma. J Clin Oncol 2002;20:4261–4267. [5] Cheson BD, Pfistner B, Juweid ME, et al. International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Letter to the Editor
Usefulness of second rituximab maintenance after relapse in patients with follicular and mantle cell lymphoma Blanca Sanchez-Gonzalez, Eva Gimeno, Francesc Garcia-Pallarols, Agueda Ancochea & Antonio Salar Department of Hematology, Hospital del Mar – IMIM, Barcelona, Spain
Rituximab–chemotherapy induction followed by maintenance therapy with rituximab is the standard front-line treatment for follicular lymphoma (FL) [1] and older patients with mantle-cell lymphoma (MCL) [2]. Currently, many patients have previously received maintenance rituximab when they relapse [3,4]. In this setting, the usefulness of a second maintenance with rituximab is unknown. We identified 10 patients with FL and three with MCL from our lymphoma registry. All patients with FL or MCL who received a second maintenance with rituximab were included in this study (Table I). All but three cases started first rituximab maintenance (RM1) in complete remission (CR) after immunotherapy or immunochemotherapy. When relapse or progression occurred, eight patients fulfilled the criteria for rituximab refractoriness. Nevertheless, all but one received rituximab-containing therapy as subsequent treatment. RM1 schedules were: 375 mg/m2/week for 4 weeks every 6 months or 375 mg/m2 every 3 months, both for 2 years or until progression. The second rituximab maintenance (RM2) schedule was: 375 mg/m2 every 3 months for 2 years or until progression. Nine patients achieved CR and four patients achieved a partial remission (PR), and then RM2 was started. While all patients who started RM2 in PR progressed during maintenance (median time to progression was 5 months), only three patients (33%) who entered RM2 in CR progressed (median time to progression was not reached; p 0.00566) (Figure 1). Interestingly, the median duration of response after RM2 was longer than after RM1 (30 vs. 18 months, respectively; p 0.656). RM2 was well tolerated with similar toxicities in comparison with RM1. No toxicities leading to RM2 discontinuation were noted. Current management of some B-cell lymphomas includes rituximab-containing chemotherapy followed by rituximab maintenance. There are no established recommendations about the role of RM2 for relapsed patients who have previously received rituximab maintenance and,
at present, this clinical situation is increasing strikingly. Within the limits of this small retrospective analysis, our results suggest that RM2 has encouraging clinical activity in those patients starting the procedure in CR according to International Working Group (IWG) response criteria [5]. RM2 is well tolerated with only minor toxicity. In addition, our findings suggest that current criteria regarding rituximab refractoriness should also be revisited, since most patients fulfilling these criteria responded to rituximabbased therapy. In conclusion, RM2 is feasible, effective and safe, and has promising activity in particular in patients starting the procedure in CR. However, prospective studies should confirm our data.
Figure 1. Time to progression from starting second rituximab maintenance to next progression or last follow-up. Kaplan–Meier curves and significance according to log-rank test. CR, complete remission; PR, partial remission.
Correspondence: Blanca Sanchez-Gonzalez, MD, PhD, Department of Hematology, Hospital del Mar, Barcelona, Spain. Tel/fax: 34-93-248-3343. E-mail: [email protected] Received 4 October 2013; accepted 24 November 2013
2384
65
53
70
3 M FL grade 2
4 M FL grade 2
5 F
72
FL grade 3A
FL grade 1
FL grade 3A
7 F
8 F
9 F
MCL
12 F
62
IV
IV
IV
IV
IV
II
IV
IV
II
III
IV
II
I
2
3
4
3
4
1
3
2
2
1
2
1
1
IPI
Treatment
R-CVP
R-CVP
R-CHOP
R-EPOCH
R-CMyOP
1st line
CVP
2nd line R-FCM
1st line
1st line
2nd line R-CMyOP
1st line
1st line
1st line
2nd line Rituximab monotherapy 3rd line Rituximab monotherapy 1st line Rituximab monotherapy 2nd line Rituximab monotherapy 1st line Chlorambucil
Line of treatment
CR
CR
CR
PR
CR
PR
CR
CR
CR
PR
CR
CR
CR
4 weeks every 6 months 4 weeks every 6 months 4 weeks every 6 months 4 weeks every 6 months 4 weeks every 6 months 1 week every 3 months 4 weeks every 6 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 4 weeks every 6 months 1 every 3 months 4 weeks every 6 months 93
20
55
25
22
13
10
11
19
12
50
82
50
70
72
75
84
86
74
74
67
73
54
71
74
85
IV
I
IV
IV
IV
II
IV
II
III
IV
IV
I
III
Age (years) Stage
2
1
2
2
2
2
2
1
3
1
3
1
2
Treatment
2nd line Rituximab monotherapy
4th line R-GEMOX
2nd line R-FCM
2nd line bendamustine
4th line R-bendamustine
2nd line R-bendamustine
2nd line R-EPOCH
2nd line R-FC
2nd line R-chlorambucil
3rd line R-CHOP
4th line Rituximab monotherapy 4th line Rituximab monotherapy 2nd line R-CVP
Line of IPI treatment
CR
CR
CR
PR
CR
PR
CR
CR
CR
CR
PR
CR
PR
1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months 1 week every 3 months
10
45
33
3
28
11
30
36
62
5
8
32
5
No
No
No
Yes
Yes
Yes
Yes
No
No
Yes
Yes
No
Yes
Duration of response Rituximab at last maintenance follow-up Response schedule (months) Relapse
Second rituximab maintenance
liposomal adriamycin, vincristine and prednisone; R-EPOCH, rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine and prednisone; R-FCM, rituximab, fludarabine, cyclophosphamide and mitoxantrone; R-FC, rituximab, fludarabine and cyclophosphamide; R-CVP, rituximab, cyclophosphamide, vincristine and prednisone; CVP, cyclophosphamide, vincristine and prednisone; R-GEMOX, rituximab, gemcitabine and oxaliplatin, R-, chlorambucil, rituximab, chlorambucil; PR, partial remission, CR, complete remission.
FL, follicular lymphoma; MCL, mantle cell lymphoma; M, male; F, female; IPI, International Prognostic Index; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-CMyOP, rituximab, cyclophosphamide,
13 M FL grade 1
70
MCL
11 F
66
81
10 M MCL
83
73
65
6 M FL grade 3A
FL grade 1
67
FL grade 2
2 F
78
FL grade 1
Age (years) Stage
1 F
ID Sex Histology
Duration Rituximab of maintenance response Response schedule (months)
First rituximab maintenance
Table I. Patient characteristics, treatments and responses during first and second rituximab maintenance.
Letter to the Editor 2385
2386 B. S. Gonzalez et al. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011;377:42–51.
[2] Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med 2012;367: 520–531. [3] van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010;28:2853–2858. [4] Hainsworth JD, Litchy S, Burris HA 3rd, et al. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma. J Clin Oncol 2002;20:4261–4267. [5] Cheson BD, Pfistner B, Juweid ME, et al. International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
