- Email: [email protected]
Rituximab Maintenance Therapy Until Progression After Rituximab and Chemotherapy Induction in Patients With Follicular Lymphoma
Original Study
Rituximab Maintenance Therapy Until Progression After Rituximab and Chemotherapy Induction in Patients With Follicular Lymphoma Jean Yared,1 Amy Kimball,1 Maria R. Baer,1 Huzefa Bahrain,2 Michael Auerbach2 Abstract The optimal duration of maintenance rituximab (MR) in follicular lymphoma (FL) is unknown. We retrospectively analyzed the outcome of 25 consecutive, unselected, previously untreated patients with low-grade high tumor burden FL who achieved a partial or complete response to induction immunochemotherapy and received ongoing MR therapy. After an average of 5.2 years of MR, progression-free survival (PFS) is still 100%, without significant toxicities. Continuous MR is safe and may prolong PFS in patients with FL. Introduction: The PRIMA (Primary Rituximab and Maintenance) study established 2 years of maintenance rituximab (MR) as a standard of care for follicular lymphoma (FL) patients who achieve an objective response after induction chemotherapy. A 17% improvement in progression-free survival (PFS) compared with those who did not receive MR was observed. However, the decision to stop MR after 2 years was arbitrary, and the PRIMA study reports only short-term follow-up of 3 years. Longer series on FL outcomes describe ubiquitous relapse and death following recurrence. The optimal duration of MR is under investigation. Herein, we report our experience with prolonged MR in FL. Patients and Methods: In this retrospective analysis, the outcome of 25 consecutive, unselected, previously untreated patients with low-grade high tumor burden FL in need for treatment is described. All patients achieved a partial or complete response to induction immunochemotherapy and received ongoing MR therapy. Results: With a median follow-up of 5.0 years and 5.2 years mean duration of MR, there are no relapses. Five deaths have occurred, unrelated to lymphoma or therapy. Prolonged MR treatment has been well-tolerated. Hypogammaglobulinemia is the only observed adverse event, with only one patient requiring monthly intravenous gamma globulin infusions due to recurrent pneumonia. There has been no discontinuation of MR or refusal to remain on MR. Conclusion: These provocative long-term results suggest that continuous MR beyond 2 years is safe and may be associated with prolonged PFS in patients with FL who achieve an objective response after immunochemotherapy. Clinical Lymphoma, Myeloma & Leukemia, Vol. 13, No. 3, 253-7 © 2013 Elsevier Inc. All rights reserved. Keywords: Rituximab, Rituximab maintenance, Prolonged rituximab maintenance, Follicular lymphoma, Indolent lymphoma
Introduction Rituximab was recently approved by the US FDA for maintenance therapy in follicular lymphoma (FL) patients who achieve at least a partial response (PR) after induction immunochemotherapy. In the international PRIMA (Primary Rituximab and Maintenance) trial, 2 years of maintenance rituximab (MR) resulted in significant prolon-
1
University of Maryland, Greenebaum Cancer Center, Baltimore, MD Auerbach Hematology/Oncology, Rosedale, MD
2
Submitted: Sep 25, 2012; Revised: Dec 17, 2012; Accepted: Dec 18, 2012; Epub: Jan 24, 2013 Address for correspondence: Michael Auerbach, MD, Auerbach Hematology/ Oncology, 9110 Philadelphia Rd, Suite 314, Rosedale, MD 21237 E-mail contact: [email protected]
2152-2650/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2012.12.011
gation of progression-free survival (PFS), with PFS of 75% in the rituximab arm, compared with 58% in the observation arm, with acceptable toxicity.1 Currently, rituximab and chemotherapy followed by 2 years of MR therapy is the standard for FL for whom treatment is indicated and who achieve at least a PR after induction. This regimen is the platform against which new therapeutic strategies should be compared. FL is still an incurable disease, and despite improved outcomes, patients still relapse and die from their disease. Defining further approaches to extend PFS, and ideally overall survival (OS), remains an essential goal. After successful induction, a maintenance strategy with a well-tolerated treatment, such as rituximab, is an appealing approach to prevent re-emergence of disease. In 2010, we reported a retrospective analysis of a single institution experience with MR until progression in patients with low-grade
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Prolonged Rituximab Maintenance in Follicular Lymphoma CD20-positive B-cell lymphoma who were candidates for chemotherapy based on current standards. This therapy was well tolerated and resulted in prolonged PFS, with no relapses.2 In this report, 2 years after our initial publication, we are updating the cohort of FL with ongoing MR.
Age, Median (Range), at Diagnosis, Years
6 (24%)
ⱖ 60
19 (76%)
Sex (Male/Female)
We analyzed clinical data on 25 consecutive, unselected, previously untreated patients with biopsy-proven FL, who achieved a PR or a complete response (CR) after systemic treatment and received MR indefinitely, until disease progression, in a single institution from 2000 to 2012. All had high tumor burden disease and at least 1 indication for initiation of systemic treatment (Tables 1 and 2) which included B symptoms, cytopenia(s), bulky disease, disease progression, or impending end organ damage. Induction consisted of 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine and prednisone) in most patients analyzed (Table 1). More recently, rituximab plus bendamustine has been used for induction. Maintenance consisted of 375 mg/m2 of rituximab weekly for 4 weeks every 16 weeks for 2 years, then 375 mg/m2 every 2 months for the balance of 5 years, then 375 mg/m2 every 3 months until occurrence of disease progression, death, or unacceptable toxicity. All patients were followed regularly with history, physical examination, blood tests including complete blood counts, serum chemistry profile, serum immunoglobulin (Ig) levels, and lactate dehydrogenase. Computed tomography (CT) or positron emission tomography/CT scans were performed quarterly the first 2 years after completion of chemotherapy and at 6- to 12-month intervals thereafter. Response and disease progression were assessed according to the International Working Group recommendations.3,4 The date of last follow-up for this analysis was April 2, 2012, and the median follow-up after initiation of therapy was 60 months. OS was estimated using the Kaplan–Meier method (Figure 1). All living patients signed informed consent to be included in this analysis.
Histology
A total of 25 consecutive, unselected patients with FL, treated with MR were included in this analysis. Patient characteristics are detailed in Tables 1 and 2. The median follow-up is 5 years (range, 1-12 years). Median age at diagnosis was 64 years (range, 39-82) and 20 of 25 patients (80%) had intermediate- or high-risk disease (Follicular Lymphoma International Prognostic Index score of 2 or ⱖ 3). The mean and median duration of MR are 63 and 54 months (range, 8-140), respectively (Figure 2). The mean and median number of rituximab doses administered are 45 and 37 (range, 8-125), respectively. After induction, 14 of 25 patients (56%) achieved CR/unconfirmed CR (CRu), and 11 of 25 (44%) achieved a PR. At the most recent follow-up imaging, 19 of 25 patients (76%) were in CR/CRu and 6 of 25 (24%) were in PR. PR improved to CR/CRu during MR in 5 of 11 patients (45.4%). At the time of last follow-up, all living patients were still receiving rituximab. To date, there has been no clinical or radiographic progression. The PFS is 100% and the lymphoma-related mortality is 0%, but the 5-year OS is 82% (Figure 1). Five non-FL related deaths occurred; 3 patients died of stroke and 2 from myocardial infarction, all of whom had known cardiovascular risk factors before the diagnosis of FL. Their ages at death were 65,
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Patients and Methods
Results
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Table 1 Patient Characteristics
Follicular
12/13 (48%/52%)
25 (100%)
WHO Grade 1
11 (44%)
2
9 (36%)
Not available
5 (20%)
Bulky Disease (> 7 cm), at Diagnosis
8 (32%)
B Symptoms, at Diagnosis
9 (36%)
ECOG Performance Status, at Diagnosis 0-1
23 (92%)
2
2 (8%)
LDH > ULN, at Diagnosis
7 (28%)
Hemoglobin < 12 g/dL, at Diagnosis
4 (16%)
Ann Arbor Staging (I-II/III-IV), at Diagnosis
5/20 (20%/80%)
FLIPI Score, at Diagnosis Low (0-1 risk factor)
4 (16%)
Intermediate (2 risk factors)
13 (52%)
High (3-5 risk factors)
8 (32%)
Induction Immunochemotherapy Regimen R-CHOP
14 (56%)
R-CVP
9 (36%)
R-FCM
1 (4%)
R-B
1 (4%)
Indication for Initiation of Induction Treatmenta B symptoms b
9 (36%)
Cytopenia(s)
5 (20%)
Bulky disease
13 (52%)
Steady progression
8 (32%)
Impending end organ damage
12 (48%)
Response to Induction CR/CRu
14 (56%)
PR
11 (44%)
Abbreviations: CR ⫽ complete response; CRu ⫽ unconfirmed complete response; ECOG ⫽ Eastern Cooperative Oncology Group; FLIPI ⫽ Follicular Lymphoma International Prognostic Index; LDH ⫽ lactate dehydrogenase; PR ⫽ partial response; R-CHOP ⫽ rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CVP ⫽ rituximab, cyclophosphamide, vincristine, and prednisone; R-FCM ⫽ rituximab, fludarabine, cyclophosphamide and mitoxantrone; ULN ⫽ upper limit of normal; WHO ⫽ World Health Organization. a The sum of the total is ⬎ 100% because many of the patients had ⬎ 1 indication for initiation of the treatment. b White blood cells ⬍ 1000 cells/L and/or platelets ⬍ 100,000/L.
77, 80, 81, and 82 years. Serum Ig levels were measured regularly. Eighty-four percent had at least 1 Ig level below the laboratory’s normal range, most commonly IgM (median, 20 g/dL; range, 4-83
Jean Yared et al Table 2 Patients FLIPI Score and Indication for Initiation of Induction Treatmenta Patient Number 1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
FLIPI Score 1
Œ
Œ
2
Œ
Œ
Œ Œ Œ
3
Œ
Œ
Œ
Œ
4
Œ Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
5
Œ
Indication for Initiation of Induction Treatment B symptoms
Œ
b
Cytopenia(s)
Œ
Œ
Œ
Œ
Bulky disease, including massive splenomegaly
Œ
Œ Œ Œ Œ
Steady progression
Œ
Œ
Impending end organ damage
Œ
Œ
Œ Œ Œ
Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
Abbreviations: FLIPI ⫽ Follicular Lymphoma International Prognostic Index; GELF ⫽ Groupe d’Etude des Lymphomes Folliculaires. a Adopted from the GELF criteria and the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: non-Hodgkin’s lymphoma, version 3.2012. b White blood cells ⬍ 1000 cells/L and/or platelets ⬍ 100,000/L.
Figure 1 Overall Survival Kaplan-Meier Estimate of the 25 Follicular Lymphoma Patients Taking Rituximab Maintenance Therapy From Initiation of the Treatment
Figure 2 Dot Plot Showing for Each Individual Patient the Duration of Rituximab Maintenance at the Time of Last Follow-Up
140 120 Time on MR (months)
Overall survival probability (%)
100 80 60 40 20
100 80 60
Average MR duration: 63 months
40 24-month line
20
Individual patient
0
0 0
2
4
6 8 Time (years)
10
12
14
g/dL), followed by IgG (median, 538 g/dL; range, 106-1062 g/dL) and IgA (median, 85 g/dL; range, 5-187 g/dL). Serious infections which necessitated intravenous (I.V.) antibiotics and hospitalization occurred in only 2 patients, and were associated with low serum IgG levels, but not neutropenia. These infections occurred after the second year of MR treatment. The first patient had recurrent pneumonias; I.V. polyvalent gamma globulin therapy was started at 400 mg/kg per month with ongoing MR, and neither infection nor progression has occurred in more than 2 years. The second patient had a pulmonary abscess because of community acquired aspiration pneumonia, unrelated to FL therapy, and was successfully treated by
Patients 1–25
drainage and I.V. antibiotics. MR was discontinued during the antimicrobial therapy and resumed thereafter and no recurrence has been observed in more than 4 years. There were no episodes of neutropenia. None of the patients were hepatitis B carriers. Second malignancies, progressive multifocal leukoencephalopathy, cytomegalovirus, or other viral infections have not been observed.
Discussion Maintenance rituximab given for 2 years has been shown to achieve dramatic improvements in PFS of FL patients who achieved at least a PR after induction rituximab, chemotherapy, or combina-
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Prolonged Rituximab Maintenance in Follicular Lymphoma tion therapy with both1,5,6 and rituximab was therefore approved by the FDA for this indication in January 2011. Nevertheless, 25%32% of these patients relapsed at 3 years,1,6 and these numbers continue to increase with time. Moreover, Vidal et al performed a systematic review and metaanalysis of randomized controlled trials comparing MR with observation in FL patients, and found an OS benefit for MR.7,8 This clear OS benefit was observed only in relapsed or refractory FL, but not after first induction.7,8 A longer follow-up might be necessary to show a statistically significant OS difference after first remission.9,10 In accordance with other studies,1,11 we observed in our series a 45% conversion from PR to CR/CRu while taking MR. The optimal dosing, schedule, and duration of MR are still undetermined, but are under active investigation. These include 1 dose every 2 months, or every 3 months, or a weekly dose for 4 weeks every 6 months, all of which have resulted in improved patient outcomes.6,12,13 The decision to stop MR at 2 years in the PRIMA1 and the ECOG14966 studies was arbitrary. The safety of 2 years of MR was studied in the PRIMA trial and no new or unexpected adverse events (AEs) were seen. RESORT (Rituximab Extended Schedule or ReTreatment Trial)14 randomized FL patients who responded after initial rituximab induction to either rituximab at onset of disease progression or indefinite MR until disease progression or unacceptable toxicity. In a recent report, the time to treatment failure was comparable in both arms.15 However, the patients included in RESORT had a low tumor burden FL and those in the PRIMA and our series had a high tumor burden FL. The SAKK (Swiss Group for Clinical Cancer Research) trial is currently evaluating MR in FL for a maximum of 5 years. Event-free survival (EFS) is the primary end point and has not been reported yet, but after a median follow-up of 3.3 years, the authors concluded that MR after 2 years is feasible and that there is no evidence of increased toxicity.16 The SAKK 35/98 trial showed that the median EFS was almost doubled for MR and that 25% of the patients receiving MR were still in remission at 8 years.13 In the StiL (Studiengruppe indolente Lymphome) NHL 7-2008 trial, the German investigators are comparing 4 years of MR to 2 years of MR in FL patients after R-B (rituximab and bendamustine) induction.17 Grade 3-4 neutropenia/infections were reported in only 3%-4% receiving MR in the PRIMA, SAKK, and MAXIMA (MAintenance rituximab for Follicular LymphoMA)18 studies. All grade 3-4 AEs were more frequent in the MR arm of the PRIMA study (24% vs. 17% in the observation arm). Rituximab causes hypogammaglobulinemia in a subset, though it is unclear whether this is associated with more frequent infections. Quality of life was specifically addressed in a German prospective randomized controlled trial,19 and in PRIMA and showed no difference between the MR and observation arms. The pharmacoeconomic aspect of MR has been well studied, demonstrating that this treatment is cost-effective, compared with observation.20-22
Conclusion Our experience with MR, with median and mean exposures of 4.5 and 5.2 years, respectively, suggests that efficacy is maintained over this period with minimal toxicity despite development of hypogammaglobulinemia. To date, in this population of high tumor burden
256
Clinical Lymphoma, Myeloma & Leukemia June 2013
FL fulfilling GELF (Groupe d’Etude des Lymphomes Folliculaires) criteria for treatment, no patients receiving continuous MR have evidence of clinical or radiographic progression precluding calculation of median PFS. The consecutive, nonselected nature of the population, all of whom had clear indications for therapy, limits bias in the interpretation of these data. Though our data are limited by a relatively small number of subjects, and the lack of a control group, our results strikingly demonstrate the efficacy of prolonged MR treatment after 2 years after induction. Our data are intriguing and support the need for corroborating prospective clinical trials to compare finite MR versus treatment until disease progression. Considering the astronomic costs of new therapies for relapsed FL, studies that address the optimal dosing and duration to assess the safest and most efficient use of MR in FL patients appear prudent.
Clinical Practice Points ●
●
●
Maintenance rituximab given for 2 years has been shown to achieve dramatic improvements in PFS of FL patients who achieved at least a PR after induction rituximab, chemotherapy, or combination therapy with both; rituximab was therefore approved by the FDA for this indication. Nevertheless, 25%-32% of these patients relapsed at 3 years. The decision to stop MR at 2 years in the PRIMA and ECOG1496 studies was arbitrary. We report our experience with continuous MR in a population of high tumor burden FL fulfilling GELF criteria who achieved an objective response to induction immunochemotherapy. With median and mean exposures of 4.5 and 5.2 years, respectively, PFS is 100% so far, which suggests that efficacy is maintained over this period with minimal toxicity. Our findings are intriguing and suggest that prolonged MR is feasible, safe, and efficacious. Our data support the need for corroborating prospective clinical trials to compare the safety and efficacy of finite MR versus treatment until disease progression.
Disclosure The authors have stated that they have no conflicts of interest.
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. Ayoola A, Terrell M, Bahrain H, Ford P, Auerbach M. Experience with maintenance rituximab after chemotherapy in patients with low-grade lymphoma. Community Oncology 2010; 7:414-7. 3. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17:1244. 4. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25:579-86. 5. Ardeshna KM, Qian W, Smith P, et al. An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2 and 3a). A preliminary analysis. ASH Annual Meeting Abstracts 2010; 116:6. 6. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 study. J Clin Oncol 2009; 27:1607-14. 7. Vidal L, Gafter-Gvili A, Leibovici L, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 2009; 101:248-55. 8. Vidal L, Gafter-Gvili A, Salles G, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 2011; 103:1799-806.
Jean Yared et al 9. Swenson WT, Wooldridge JE, Lynch CF, et al. Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 2005; 23:5019-26. 10. Pulte D, Gondos A, Brenner H. Ongoing improvement in outcomes for patients diagnosed as having non-Hodgkin lymphoma from the 1990s to the early 21st century. Arch Intern Med 2008; 168:469-76. 11. Schneider TJ, Rosta A, Losonczy H, et al. Results of the interim analysis of the ‘HUSOM’ trial: Hungarian study of maintenance after rituximab pretreatment, a multicentre, phase III, open-label study evaluating the benefit of a long-term MabThera (rituximab) maintenance therapy in patients with advance follicular lymphoma after induction of response (CR(u) or PR) with a MabThera (rituximab)containing first line regimen. ASH Annual Meeting Abstracts 2011; 118:2714. 12. van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006; 108:3295-301. 13. Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 2010; 28:4480-4. 14. Kahl BS, Williams ME, Hong F, et al. Preliminary pharmacokinetic (PK) analysis of Eastern Cooperative Oncology Group Protocol E4402: Rituximab Extended Schedule or Re-Treatment Trial (RESORT). ASH Annual Meeting Abstracts 2007; 110:3420. 15. Kahl BS, Hong F, Williams ME, et al. Results of Eastern Cooperative Oncology Group Protocol E4402. RESORT: a randomized phase III study comparing two
16. 17. 18.
19.
20.
21. 22.
different rituximab dosing strategies for low tumor burden follicular lymphoma. ASH Annual Meeting Abstracts 2011; 118:LBA-6. Taverna CJ, Bassi S, Hitz F, et al. Rituximab maintenance treatment for a maximum of 5 years in follicular lymphoma: safety analysis of the randomized phase III trial SAKK 35/03. ASH Annual Meeting Abstracts 2010; 116:1802. Rummel M. Reassessing the standard of care in indolent lymphoma: a clinical update to improve clinical practice. J Natl Compr Cancer Netw 2010; 8:S1-14. Foa R, Di Rocco A, van Hazel G, et al. Maintenance rituximab every 2 months for 2 years is effective and well tolerated in patients with follicular lymphoma with both standard or rapid infusion: updated results from the phase IIIb MAXIMA study. ASH Annual Meeting Abstracts 2010; 116:3945. Witzens-Harig M, Reiz M, Heiss C, et al. Quality of life during maintenance therapy with the anti-CD20 antibody rituximab in patients with B cell non-Hodgkin’s lymphoma: results of a prospective randomized controlled trial. Ann Hematol 2009; 88:51-7. Papadakis K, Follows GA, Boyer J, et al. Cost effectiveness analysis of rituximab maintenance in patients with untreated high tumour burden follicular lymphoma after response to immunochemotherapy: a UK national healthcare services perspective. ASH Annual Meeting Abstracts 2010; 116:3833. Kasteng F, Erlanson M, Hagberg H, et al. Cost-effectiveness of maintenance rituximab treatment after second line therapy in patients with follicular lymphoma in Sweden. Acta Oncol 2008; 47:1029-36. Deconinck E, Miadi-Fargier H, Pen CL, et al. Cost effectiveness of rituximab maintenance therapy in follicular lymphoma: long-term economic evaluation. Pharmacoeconomics 2010; 28:35-46.
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Rituximab Maintenance Therapy Until Progression After Rituximab and Chemotherapy Induction in Patients With Follicular Lymphoma Jean Yared,1 Amy Kimball,1 Maria R. Baer,1 Huzefa Bahrain,2 Michael Auerbach2 Abstract The optimal duration of maintenance rituximab (MR) in follicular lymphoma (FL) is unknown. We retrospectively analyzed the outcome of 25 consecutive, unselected, previously untreated patients with low-grade high tumor burden FL who achieved a partial or complete response to induction immunochemotherapy and received ongoing MR therapy. After an average of 5.2 years of MR, progression-free survival (PFS) is still 100%, without significant toxicities. Continuous MR is safe and may prolong PFS in patients with FL. Introduction: The PRIMA (Primary Rituximab and Maintenance) study established 2 years of maintenance rituximab (MR) as a standard of care for follicular lymphoma (FL) patients who achieve an objective response after induction chemotherapy. A 17% improvement in progression-free survival (PFS) compared with those who did not receive MR was observed. However, the decision to stop MR after 2 years was arbitrary, and the PRIMA study reports only short-term follow-up of 3 years. Longer series on FL outcomes describe ubiquitous relapse and death following recurrence. The optimal duration of MR is under investigation. Herein, we report our experience with prolonged MR in FL. Patients and Methods: In this retrospective analysis, the outcome of 25 consecutive, unselected, previously untreated patients with low-grade high tumor burden FL in need for treatment is described. All patients achieved a partial or complete response to induction immunochemotherapy and received ongoing MR therapy. Results: With a median follow-up of 5.0 years and 5.2 years mean duration of MR, there are no relapses. Five deaths have occurred, unrelated to lymphoma or therapy. Prolonged MR treatment has been well-tolerated. Hypogammaglobulinemia is the only observed adverse event, with only one patient requiring monthly intravenous gamma globulin infusions due to recurrent pneumonia. There has been no discontinuation of MR or refusal to remain on MR. Conclusion: These provocative long-term results suggest that continuous MR beyond 2 years is safe and may be associated with prolonged PFS in patients with FL who achieve an objective response after immunochemotherapy. Clinical Lymphoma, Myeloma & Leukemia, Vol. 13, No. 3, 253-7 © 2013 Elsevier Inc. All rights reserved. Keywords: Rituximab, Rituximab maintenance, Prolonged rituximab maintenance, Follicular lymphoma, Indolent lymphoma
Introduction Rituximab was recently approved by the US FDA for maintenance therapy in follicular lymphoma (FL) patients who achieve at least a partial response (PR) after induction immunochemotherapy. In the international PRIMA (Primary Rituximab and Maintenance) trial, 2 years of maintenance rituximab (MR) resulted in significant prolon-
1
University of Maryland, Greenebaum Cancer Center, Baltimore, MD Auerbach Hematology/Oncology, Rosedale, MD
2
Submitted: Sep 25, 2012; Revised: Dec 17, 2012; Accepted: Dec 18, 2012; Epub: Jan 24, 2013 Address for correspondence: Michael Auerbach, MD, Auerbach Hematology/ Oncology, 9110 Philadelphia Rd, Suite 314, Rosedale, MD 21237 E-mail contact: [email protected]
2152-2650/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2012.12.011
gation of progression-free survival (PFS), with PFS of 75% in the rituximab arm, compared with 58% in the observation arm, with acceptable toxicity.1 Currently, rituximab and chemotherapy followed by 2 years of MR therapy is the standard for FL for whom treatment is indicated and who achieve at least a PR after induction. This regimen is the platform against which new therapeutic strategies should be compared. FL is still an incurable disease, and despite improved outcomes, patients still relapse and die from their disease. Defining further approaches to extend PFS, and ideally overall survival (OS), remains an essential goal. After successful induction, a maintenance strategy with a well-tolerated treatment, such as rituximab, is an appealing approach to prevent re-emergence of disease. In 2010, we reported a retrospective analysis of a single institution experience with MR until progression in patients with low-grade
Clinical Lymphoma, Myeloma & Leukemia June 2013
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Prolonged Rituximab Maintenance in Follicular Lymphoma CD20-positive B-cell lymphoma who were candidates for chemotherapy based on current standards. This therapy was well tolerated and resulted in prolonged PFS, with no relapses.2 In this report, 2 years after our initial publication, we are updating the cohort of FL with ongoing MR.
Age, Median (Range), at Diagnosis, Years
6 (24%)
ⱖ 60
19 (76%)
Sex (Male/Female)
We analyzed clinical data on 25 consecutive, unselected, previously untreated patients with biopsy-proven FL, who achieved a PR or a complete response (CR) after systemic treatment and received MR indefinitely, until disease progression, in a single institution from 2000 to 2012. All had high tumor burden disease and at least 1 indication for initiation of systemic treatment (Tables 1 and 2) which included B symptoms, cytopenia(s), bulky disease, disease progression, or impending end organ damage. Induction consisted of 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine and prednisone) in most patients analyzed (Table 1). More recently, rituximab plus bendamustine has been used for induction. Maintenance consisted of 375 mg/m2 of rituximab weekly for 4 weeks every 16 weeks for 2 years, then 375 mg/m2 every 2 months for the balance of 5 years, then 375 mg/m2 every 3 months until occurrence of disease progression, death, or unacceptable toxicity. All patients were followed regularly with history, physical examination, blood tests including complete blood counts, serum chemistry profile, serum immunoglobulin (Ig) levels, and lactate dehydrogenase. Computed tomography (CT) or positron emission tomography/CT scans were performed quarterly the first 2 years after completion of chemotherapy and at 6- to 12-month intervals thereafter. Response and disease progression were assessed according to the International Working Group recommendations.3,4 The date of last follow-up for this analysis was April 2, 2012, and the median follow-up after initiation of therapy was 60 months. OS was estimated using the Kaplan–Meier method (Figure 1). All living patients signed informed consent to be included in this analysis.
Histology
A total of 25 consecutive, unselected patients with FL, treated with MR were included in this analysis. Patient characteristics are detailed in Tables 1 and 2. The median follow-up is 5 years (range, 1-12 years). Median age at diagnosis was 64 years (range, 39-82) and 20 of 25 patients (80%) had intermediate- or high-risk disease (Follicular Lymphoma International Prognostic Index score of 2 or ⱖ 3). The mean and median duration of MR are 63 and 54 months (range, 8-140), respectively (Figure 2). The mean and median number of rituximab doses administered are 45 and 37 (range, 8-125), respectively. After induction, 14 of 25 patients (56%) achieved CR/unconfirmed CR (CRu), and 11 of 25 (44%) achieved a PR. At the most recent follow-up imaging, 19 of 25 patients (76%) were in CR/CRu and 6 of 25 (24%) were in PR. PR improved to CR/CRu during MR in 5 of 11 patients (45.4%). At the time of last follow-up, all living patients were still receiving rituximab. To date, there has been no clinical or radiographic progression. The PFS is 100% and the lymphoma-related mortality is 0%, but the 5-year OS is 82% (Figure 1). Five non-FL related deaths occurred; 3 patients died of stroke and 2 from myocardial infarction, all of whom had known cardiovascular risk factors before the diagnosis of FL. Their ages at death were 65,
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Results
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Table 1 Patient Characteristics
Follicular
12/13 (48%/52%)
25 (100%)
WHO Grade 1
11 (44%)
2
9 (36%)
Not available
5 (20%)
Bulky Disease (> 7 cm), at Diagnosis
8 (32%)
B Symptoms, at Diagnosis
9 (36%)
ECOG Performance Status, at Diagnosis 0-1
23 (92%)
2
2 (8%)
LDH > ULN, at Diagnosis
7 (28%)
Hemoglobin < 12 g/dL, at Diagnosis
4 (16%)
Ann Arbor Staging (I-II/III-IV), at Diagnosis
5/20 (20%/80%)
FLIPI Score, at Diagnosis Low (0-1 risk factor)
4 (16%)
Intermediate (2 risk factors)
13 (52%)
High (3-5 risk factors)
8 (32%)
Induction Immunochemotherapy Regimen R-CHOP
14 (56%)
R-CVP
9 (36%)
R-FCM
1 (4%)
R-B
1 (4%)
Indication for Initiation of Induction Treatmenta B symptoms b
9 (36%)
Cytopenia(s)
5 (20%)
Bulky disease
13 (52%)
Steady progression
8 (32%)
Impending end organ damage
12 (48%)
Response to Induction CR/CRu
14 (56%)
PR
11 (44%)
Abbreviations: CR ⫽ complete response; CRu ⫽ unconfirmed complete response; ECOG ⫽ Eastern Cooperative Oncology Group; FLIPI ⫽ Follicular Lymphoma International Prognostic Index; LDH ⫽ lactate dehydrogenase; PR ⫽ partial response; R-CHOP ⫽ rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CVP ⫽ rituximab, cyclophosphamide, vincristine, and prednisone; R-FCM ⫽ rituximab, fludarabine, cyclophosphamide and mitoxantrone; ULN ⫽ upper limit of normal; WHO ⫽ World Health Organization. a The sum of the total is ⬎ 100% because many of the patients had ⬎ 1 indication for initiation of the treatment. b White blood cells ⬍ 1000 cells/L and/or platelets ⬍ 100,000/L.
77, 80, 81, and 82 years. Serum Ig levels were measured regularly. Eighty-four percent had at least 1 Ig level below the laboratory’s normal range, most commonly IgM (median, 20 g/dL; range, 4-83
Jean Yared et al Table 2 Patients FLIPI Score and Indication for Initiation of Induction Treatmenta Patient Number 1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
FLIPI Score 1
Œ
Œ
2
Œ
Œ
Œ Œ Œ
3
Œ
Œ
Œ
Œ
4
Œ Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
5
Œ
Indication for Initiation of Induction Treatment B symptoms
Œ
b
Cytopenia(s)
Œ
Œ
Œ
Œ
Bulky disease, including massive splenomegaly
Œ
Œ Œ Œ Œ
Steady progression
Œ
Œ
Impending end organ damage
Œ
Œ
Œ Œ Œ
Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
Œ
Œ
Œ Œ
Œ
Œ
Abbreviations: FLIPI ⫽ Follicular Lymphoma International Prognostic Index; GELF ⫽ Groupe d’Etude des Lymphomes Folliculaires. a Adopted from the GELF criteria and the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: non-Hodgkin’s lymphoma, version 3.2012. b White blood cells ⬍ 1000 cells/L and/or platelets ⬍ 100,000/L.
Figure 1 Overall Survival Kaplan-Meier Estimate of the 25 Follicular Lymphoma Patients Taking Rituximab Maintenance Therapy From Initiation of the Treatment
Figure 2 Dot Plot Showing for Each Individual Patient the Duration of Rituximab Maintenance at the Time of Last Follow-Up
140 120 Time on MR (months)
Overall survival probability (%)
100 80 60 40 20
100 80 60
Average MR duration: 63 months
40 24-month line
20
Individual patient
0
0 0
2
4
6 8 Time (years)
10
12
14
g/dL), followed by IgG (median, 538 g/dL; range, 106-1062 g/dL) and IgA (median, 85 g/dL; range, 5-187 g/dL). Serious infections which necessitated intravenous (I.V.) antibiotics and hospitalization occurred in only 2 patients, and were associated with low serum IgG levels, but not neutropenia. These infections occurred after the second year of MR treatment. The first patient had recurrent pneumonias; I.V. polyvalent gamma globulin therapy was started at 400 mg/kg per month with ongoing MR, and neither infection nor progression has occurred in more than 2 years. The second patient had a pulmonary abscess because of community acquired aspiration pneumonia, unrelated to FL therapy, and was successfully treated by
Patients 1–25
drainage and I.V. antibiotics. MR was discontinued during the antimicrobial therapy and resumed thereafter and no recurrence has been observed in more than 4 years. There were no episodes of neutropenia. None of the patients were hepatitis B carriers. Second malignancies, progressive multifocal leukoencephalopathy, cytomegalovirus, or other viral infections have not been observed.
Discussion Maintenance rituximab given for 2 years has been shown to achieve dramatic improvements in PFS of FL patients who achieved at least a PR after induction rituximab, chemotherapy, or combina-
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Prolonged Rituximab Maintenance in Follicular Lymphoma tion therapy with both1,5,6 and rituximab was therefore approved by the FDA for this indication in January 2011. Nevertheless, 25%32% of these patients relapsed at 3 years,1,6 and these numbers continue to increase with time. Moreover, Vidal et al performed a systematic review and metaanalysis of randomized controlled trials comparing MR with observation in FL patients, and found an OS benefit for MR.7,8 This clear OS benefit was observed only in relapsed or refractory FL, but not after first induction.7,8 A longer follow-up might be necessary to show a statistically significant OS difference after first remission.9,10 In accordance with other studies,1,11 we observed in our series a 45% conversion from PR to CR/CRu while taking MR. The optimal dosing, schedule, and duration of MR are still undetermined, but are under active investigation. These include 1 dose every 2 months, or every 3 months, or a weekly dose for 4 weeks every 6 months, all of which have resulted in improved patient outcomes.6,12,13 The decision to stop MR at 2 years in the PRIMA1 and the ECOG14966 studies was arbitrary. The safety of 2 years of MR was studied in the PRIMA trial and no new or unexpected adverse events (AEs) were seen. RESORT (Rituximab Extended Schedule or ReTreatment Trial)14 randomized FL patients who responded after initial rituximab induction to either rituximab at onset of disease progression or indefinite MR until disease progression or unacceptable toxicity. In a recent report, the time to treatment failure was comparable in both arms.15 However, the patients included in RESORT had a low tumor burden FL and those in the PRIMA and our series had a high tumor burden FL. The SAKK (Swiss Group for Clinical Cancer Research) trial is currently evaluating MR in FL for a maximum of 5 years. Event-free survival (EFS) is the primary end point and has not been reported yet, but after a median follow-up of 3.3 years, the authors concluded that MR after 2 years is feasible and that there is no evidence of increased toxicity.16 The SAKK 35/98 trial showed that the median EFS was almost doubled for MR and that 25% of the patients receiving MR were still in remission at 8 years.13 In the StiL (Studiengruppe indolente Lymphome) NHL 7-2008 trial, the German investigators are comparing 4 years of MR to 2 years of MR in FL patients after R-B (rituximab and bendamustine) induction.17 Grade 3-4 neutropenia/infections were reported in only 3%-4% receiving MR in the PRIMA, SAKK, and MAXIMA (MAintenance rituximab for Follicular LymphoMA)18 studies. All grade 3-4 AEs were more frequent in the MR arm of the PRIMA study (24% vs. 17% in the observation arm). Rituximab causes hypogammaglobulinemia in a subset, though it is unclear whether this is associated with more frequent infections. Quality of life was specifically addressed in a German prospective randomized controlled trial,19 and in PRIMA and showed no difference between the MR and observation arms. The pharmacoeconomic aspect of MR has been well studied, demonstrating that this treatment is cost-effective, compared with observation.20-22
Conclusion Our experience with MR, with median and mean exposures of 4.5 and 5.2 years, respectively, suggests that efficacy is maintained over this period with minimal toxicity despite development of hypogammaglobulinemia. To date, in this population of high tumor burden
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FL fulfilling GELF (Groupe d’Etude des Lymphomes Folliculaires) criteria for treatment, no patients receiving continuous MR have evidence of clinical or radiographic progression precluding calculation of median PFS. The consecutive, nonselected nature of the population, all of whom had clear indications for therapy, limits bias in the interpretation of these data. Though our data are limited by a relatively small number of subjects, and the lack of a control group, our results strikingly demonstrate the efficacy of prolonged MR treatment after 2 years after induction. Our data are intriguing and support the need for corroborating prospective clinical trials to compare finite MR versus treatment until disease progression. Considering the astronomic costs of new therapies for relapsed FL, studies that address the optimal dosing and duration to assess the safest and most efficient use of MR in FL patients appear prudent.
Clinical Practice Points ●
●
●
Maintenance rituximab given for 2 years has been shown to achieve dramatic improvements in PFS of FL patients who achieved at least a PR after induction rituximab, chemotherapy, or combination therapy with both; rituximab was therefore approved by the FDA for this indication. Nevertheless, 25%-32% of these patients relapsed at 3 years. The decision to stop MR at 2 years in the PRIMA and ECOG1496 studies was arbitrary. We report our experience with continuous MR in a population of high tumor burden FL fulfilling GELF criteria who achieved an objective response to induction immunochemotherapy. With median and mean exposures of 4.5 and 5.2 years, respectively, PFS is 100% so far, which suggests that efficacy is maintained over this period with minimal toxicity. Our findings are intriguing and suggest that prolonged MR is feasible, safe, and efficacious. Our data support the need for corroborating prospective clinical trials to compare the safety and efficacy of finite MR versus treatment until disease progression.
Disclosure The authors have stated that they have no conflicts of interest.
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