Hematologic Malignancies
Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Is It a Valid Treatment Option? PATRIZIA MONDELLO,a,b,c NORMANN STEINER,d WOLFGANG WILLENBACHER,d SIMONE FERRERO,e PAOLA GHIONE,e ALESSANDRA MARABESE,f VINCENZO PITINI,a SALVATORE CUZZOCREA,b MICHAEL MIANd,f a Department of Human Pathology and bDepartment of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Messina, Italy; cLymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA; dInternal Medicine V, Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; eDivision of Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy; fDepartment of Hematology and Center for Bone Marrow Transplantation, Ospedale di Bolzano, Bolzano, Italy
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Diffuse large B-cell lymphoma x Lenalidomide x Immunomodulatory drug x Relapsed/refractory lymphoma
ABSTRACT Background. Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease. Prospective clinical trials have demonstrated that lenalidomide is an effective and safe treatment option, especially for non-germinal center B-cell (non-GCB) DLBCL. However, routine clinical data are lacking, which is why we provide the results of the so-far largest relapsed/refractory (R/R) DLBCL real-life analysis. Methods. We retrospectively assessed 123 R/R DLBCL patients who received either 15 or 25 mg/day of lenalidomide from January 2006 to January 2015. Results. During a median follow-up period of 4.5 years, complete remission was achieved in 32% and a partial remission in 33% non-GCB patients compared with 0% and 3% in the
GCB group (p , .001 and .001, respectively), with median response durations of 15 and 5 months, respectively (p , .001). Lenalidomide at 25 mg was superior to 15 mg in terms of response (complete remission 21% and partial remission 23% vs. 0% and 8%; p 5 .007 and .05) and median response duration (10 vs. 4 months; p 5 .03). Toxicity was limited and reversible. Median progression-free survival differed between non-GCB and GCB patients (37 vs. 30 months; p , .001) and between the two dosages (24 vs. 34 months; p 5 .002). However, overall survival was similar between the subgroups (38–42 months). Conclusion. We provide evidence that lenalidomide is a valid treatment option for R/R DLBCL, with limited and reversible toxicity, and is more efficient in non-GCB DLBCL and at higher doses. The Oncologist 2016;21:1107–1112
Implications for Practice: Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease; hence, novel therapeutic approaches are urgently needed. This study confirms that lenalidomide is a valid and well-tolerated treatment option for relapsed/refractory (R/R) DLBCL. Superior outcomes were observed in non-germinal center B-cell (GCB) DLBCL, probably because of inhibition of the nuclear factor-kB pathway. Similarly, high drug doses resulted in greater clinical benefits. Overall, lenalidomide is a suitable therapeutic option for R/R DLBCL, especially in nonGCB DLBCL, and 25 mg/day dosing should be preferred.
INTRODUCTION Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for approximately 30% of new cases of non-Hodgkin’s lymphoma (NHL) [1]. Despite its uniform morphology, DLBCL is a very heterogeneous disease at the molecular level. By gene expression profiling (GEP), DLBCL is classifiable into two main subgroups based on the cell of origin (COO), namely the germinal center B cell (GCB) and the activated B cell (ABC) [2, 3]. However, GEP is not routinely available because of the lack of standardized commercial
tests and the need for fresh frozen tissue samples. Although methodologies based on paraffin are currently under development [4], RNA extraction yields are low, and more importantly, the RNA obtained is heavily degraded and chemically modified [5]. Several attempts have been made to correlate the two subtypes with immunohistochemical (IHC) markers [6–8].The Hans algorithm is the most commonly used and distinguishes non-GCB and GCB patients [8]. Although these algorithms provide a practical method for
Correspondence: Patrizia Mondello, M.D., M.Sc., Lymphoma Department, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.Telephone: 917-353-5554; E-Mail: [email protected] Received March 12, 2016; accepted for publication April 5, 2016; published Online First on July 5, 2016. ©AlphaMed Press 1083-7159/2016/$20.00/0 http://dx.doi.org/10.1634/theoncologist.20160103
The Oncologist 2016;21:1107–1112 www.TheOncologist.com
©AlphaMed Press 2016
Lenalidomide in Relapsed/Refractory DLBCL
1108
designating subtypes, they are a suboptimal alternative to GEP [9]. COO subtypes are characterized by distinct oncogenic driver pathways, such as the dysregulation of nuclear factor (NF)-kB pathway in ABC, resulting in variable susceptibility to different antineoplastic drugs and variable prognoses [10, 11]. In particular, the cure rate of approximately 40% in ABC DLBCL after standard immunochemotherapy is significantly inferior to that of GCB [12]. Therefore, novel therapeutic approaches targeting these different pathways are urgently needed for such patients, especially those with relapsed/refractory (R/R) disease. Recently, lenalidomide, an immunomodulatory drug, has emerged as an attractive therapeutic option for patients with NHL, including ABC DLBCL [13–17]. Lenalidomide can stimulate the innate immune system, potentiate the antitumor activity of rituximab, and inhibit angiogenesis [18, 19]. These effects can be explained by the ability to inhibit tumor necrosis factor-a, vascular endothelial growth factor, and NF-kB in cancer cells [19, 20]. Two phase 2 trials, NHL-002 and NHL-003 [13, 21], reported an overall response rate (ORR) of approximately 28%, with complete response (CR) of 7%–12%, after lenalidomide monotherapy in R/R DLBCL. Responses were durable, with a median response duration of 4.6 months.The treatment was usually well tolerated. Grade 3/4 toxicity was mainly hematologic (neutropenia and thrombocytopenia) and reversible after lenalidomide dose reduction [13, 14]. Hernandez-Ilizaliturri et al. [22] demonstrated that lenalidomide was more effective in non-GCB-like than GCB-like DLBCL in the R/R setting. However, Wang et al. [15] did not observe any variation in clinical responses using the lenalidomiderituximab combination according to the COO. Up to now, there has been no large real-life analysis assessing the efficacy and toxicity of lenalidomide in R/R DLBCL. This is of major importance, because patients enrolled in clinical trials are often highly selected, and consequently their results do not reflect clinical practice. Therefore, we retrospectively assessed 123 consecutive R/R DLBCL patients treated with lenalidomide in three European cancer centers, with the aim of evaluating efficacy and toxicity in the whole group and in the main biological subgroups according to the COO by immunohistochemistry.
were based on physician’s choice. In the case of neutropenia, granulocyte-colony stimulating factors were used at the investigators’ discretion. Response to therapy was evaluated according to Cheson et al. [24, 25] and toxicity according to the Common Terminology Criteria for Adverse Events v4.0 (http:// ctep.cancer.gov/protocolDevelopment/electronic_applications/ ctc.htm). Treatment response was assessed approximately 3 months after start of treatment by a full physical examination, blood tests, and bone marrow aspirate and biopsy in case of bone marrow involvement at diagnosis. Eighty-seven patients (71%) underwent imaging studies (computed tomography).
Statistical Analyses The x 2 test was performed to assess the significance of differences between categorical variables. Overall survival (OS), progression-free survival (PFS), and disease-free survival were defined according to Cheson et al. [24] and were plotted as curves using the Kaplan-Meier method [23]. The log-rank test was used to assess the impact of categorical variables on survival. Statistical analyses were performed with MedCalc (version 11.0; MedCalc Software, Ostend, Belgium, http:// www.medcalc.org) and GraphPad Prism (version 5.0; GraphPad, San Diego, CA, http://www.graphpad.com). The limit of significance for all analyses was defined as p , .05.
RESULTS Patient Characteristics at Start of Treatment Fifty-seven patients (46%) had GCB DLBCL, and the remaining 66 (54%) were classified into the non-GCB group. Clinical features are summarized in Table 1 and were similar between patients with GCB and non-GCB (data not shown). Overall, the median age at time of diagnosis was 64 years (range, 29–85). A male predominance was observed (75/123, 61%). Most patients had stage III or IV disease (101/123, 82%), B symptoms (75/123, 61%), bone marrow involvement (63/123, 51%), elevated lactate dehydrogenase (81/123, 66%), and elevated b2-microglobulin (66/123, 54%). Only a minority (n 5 30, 24%) had bulky disease, defined as a tumor mass of $5 cm. All patients underwent at least 1 treatment line (range 1–3), and 19% underwent autologous stem cell transplantation.
Treatment and Response METHODS Patients We retrospectively assessed 123 consecutive patients affected by R/R DLBCL in three cancer centers, two Italian and one Austrian, from January 2006 to January 2015. Histologic diagnosis was performed according to World Health Organization criteria by an expert pathologist at each participating center [23]. All patients $18 years or older with R/R DLBCL, regardless of disease stage, were included. This analysis was approved by the local ethics committees.
Treatment Plan Patients received a starting dose of either 15 or 25 mg/day of lenalidomide for 21 days of a 28-day cycle until disease progression or relapse.The initial dosing and dose adjustments
Overall, 909 cycles were administered to 123 patients, with 24 (20%) patients receiving 15 mg/day (GCB, n 5 13; non-GCB, n 5 11) and 99 (80%) patients receiving 25 mg/day (GCB, n 5 44; non-GCB, n 5 55). ORR was 37%, CR 21%, and partial remission (PR) 24%. Response to therapy was observed mainly in the patients who had at least stable disease with previous treatments compared with refractory disease (CR 22% vs. 0%, p 5 .007; PR 23% vs. 7%, p 5 .05). Progressive disease was similar between these two groups of patients (52% vs. 67%, p 5 .18). ORR differed significantly between the two IHC subtypes and was higher in non-GCB than GCB (65% vs. 3%; p , .0001) (Table 2). More patients with non-GCB achieved a CR or PR (32% and 33%, respectively) than patients with GCB (0% and 3%, respectively; p , .0001 and p 5 .001, respectively). The median response time was 5 months (range, 4–7) in the GCB group and 2 months (range, 2–3) in the non-GCB group (p 5 .02). Similarly, ORR varied according to lenalidomide dose and
OTncologist he
©AlphaMed Press 2016
®
Mondello, Steiner, Willenbacher et al.
1109
Table 1. Patient characteristics (n 5 123). Parameter Age, years Median .60 Sex Female Male IHC lymphoma subtype GCB Non-GCB B symptoms Bone marrow involvement Bulky disease .2 extranodal sites Elevated lactate dehydrogenase Elevated b2-microglobulin Ki-67 .30% Stage I II III IV Baseline performance status .1 IPI prognostic group Low risk (0–1 risk factors) Low-intermediate risk (2 risk factors) High-intermediate risk (3 risk factors) High risk (4–5 risk factors) Median time from diagnosis to first dose of lenalidomide, months (range) Median number of treatment regimens (range) Prior radiotherapy Prior autologous stem cell transplantation
Value 64 87 (71) 48 (39) 75 (61) 57 (46) 66 (54) 75 (61) 63 (51) 30 (24) 51 (41) 81 (66) 66 (54) 84 (69) 3 (2) 19 (15) 23 (19) 78 (64) 21 (17) 6 (5) 24 (20) 51 (41) 42 (34) 23 (3–92) 1 (1–3) 60 (49) 23 (19)
Data are presented as n (%) unless noted otherwise. Abbreviations: GCB, germinal center B cell; IHC, immunohistochemical; IPI, International Prognostic Index.
was higher in patients receiving 25 mg/day than in those receiving 15 mg/day (44% vs. 8%; p 5 .002). The CR rate for patients receiving 25 mg/day was 21% versus 0% for 15 mg/day (p 5 .007), and the PR rate was 23% versus 8% (p 5 .05). The median response time was 3 months (range, 2–6) in those who received 25 mg/day and 4 months (range, 3–7) in those who received 15 mg/day (not significant). Lenalidomide was well tolerated. The most common adverse event of any grade and cause was reversible myelosuppression. Grade 1/2 hematologic toxicity consisted mainly of anemia (n 5 22, 18%) followed by neutropenia (n 5 7, 6%) and thrombocytopenia (n 5 7, 6%). Hematologic grade 3/4 toxicity consisted of neutropenia (n 5 29, 24%) and thrombocytopenia (n 5 13, 11%); grade 3/4 anemia did not occur. Myeloid growth factors were administered to 22 patients (18%). Grade 3/4 febrile neutropenia occurred in only 4 patients (3%). Grade 3/4 nonhematologic events were
www.TheOncologist.com
uncommon, consisting of elevated transaminases (n 5 2, 2%) and neuropathy (n 5 1, 1%). In contrast, nonhematologic adverse events of grade 1/2 were more commonly observed. In particular, almost half of the cohort experienced peripheral neuropathy (n 5 64, 52%) and fatigue (n 5 53, 43%). Toxicity was reversible in all cases. Eight patients receiving 25 mg/day lenalidomide (8%) required dose reduction (n 5 6, 6%) or treatment interruption because of toxicity (n 5 2, 2%). The median time to first dose reduction or treatment interruption was 9 weeks, corresponding to the third treatment cycle (range, 1–5 cycles). Among the 6 patients who required dose reduction, 2 required only 1 reduction (to 20 mg) and 4 had 2 dose reductions (to 15 mg). The most common reasons for dose reduction were neutropenia (83%) and thrombocytopenia (17%). Treatment interruptions were typically brief, lasting a median of 9 days (range, 6–16 days).
Follow-Up The median follow-up was 4.5 years (range, 2–108 months). In the whole cohort, progressive disease (PD) during lenalidomide treatment occurred in 68 patients (55%). Fifty-one patients (90%) of the GCB group experienced PD compared with 17 (26%) in the non-GCB group (p , .0001). PD also varied according to lenalidomide dose: 19 patients (79%) who received 15 mg/day had PD, whereas 44 (49%) who received 25 mg/day (p 5 .02) had PD. The overall median duration of response, defined as time from maximum response until PD, was 9 months (range, 1–23 months), 5 months (range, 1–10) in the GCB group and 15 months (range, 5–23) in the non-GCB group (p , .0001). The median duration of CR, calculable only for patients with non-GCB DLBCL who received 25 mg/day lenalidomide, was 14 months (range, 5–23). Duration of remission also depended on lenalidomide dose and was 4 months (range, 1–9) in the 15-mg group and 10 months (range, 2–23) in the 25-mg group (p 5 .03). Overall, the median PFS was 34 months (range, 2–108), 37 months (range, 9–108) in the non-GCB group and 30 months (range, 2–74) in the GCB group (p , .0001) (Fig. 1). Similarly, patients in the 25-mg group achieved a longer median PFS of 34 months (range, 5–108) versus 24 months (range, 2–54; p 5 .002) in the 15-mg group. However, OS did not differ significantly between the subgroups (38 vs. 41 months in nonGCB and GCB, respectively, p 5 .2; 38 vs. 42 months in 15- and 25-mg groups) (Fig. 2).
DISCUSSION Up to now, the safety and efficacy of single-agent lenalidomide for the treatment of hematologic malignancies have been investigated intensively in many prospective clinical trials [13–15, 21]. Although it has emerged as a valid treatment option in these selected patient cohorts, live data are lacking. Therefore, we retrospectively assessed the so-far largest R/R DLBCL cohort to undergo lenalidomide monotherapy in clinical practice. Herein, we provide evidence that lenalidomide is a safe and effective treatment option for this patient setting. However, the best responses were observed in the non-GCB group and those who received 25 mg/day. The strengths of this analysis were the relatively long follow-up (nearly twice that of previous reports) [13, 22, 26] ©AlphaMed Press 2016
Lenalidomide in Relapsed/Refractory DLBCL
1110
Table 2. Best overall response by lenalidomide dose and IHC lymphoma subtype. Lenalidomide dose
IHC lymphoma subtype
Best overall response
15 mg/day
25 mg/day
GCB
Non-GCB
Overall
n Overall response Complete response Partial response Stable disease Progression of disease Previous therapeutic line(s) Time to response, months Duration of response, months Disease-free survival, months Progression-free survival, months Overall survival, months
24 2 (8) 0 (0) 2 (8) 3 (13) 19 (79) 1 (1–2) 4 (3–7) 4 (1–9) 0 (0) 24 (2–54) 38 (7–81)
99 44 (44) 21 (21) 22 (23) 7 (7) 44 (49) 2 (2–5) 3 (2–6) 10 (2–23) 14 (5–23) 34 (5–108) 42 (10–127)
57 2 (3) 0 (0) 2 (3) 4 (7) 51 (90) 2 (1–5) 5 (4–7) 5 (1–10) 0 (0) 30 (2–74) 41 (18–68)
66 44 (65) 21 (32) 22 (33) 6 (9) 17 (26) 2 (0–3) 2 (2–3) 15 (5–23) 14 (5–23) 37 (9–108) 38 (7–127)
123 46 (37) 21 (17) 24 (20) 10 (8) 68 (55) 2 (0–5) 4 (2–7) 9 (1–23) 14 (5–23) 34 (2–108) 37 (7–127)
Data are presented as n (%) or mean (range). Abbreviations: GCB, germinal center B cell; IHC, immunohistochemical.
Figure 1. Kaplan-Meier analysis of progression-free survival for all patients (A) and by DLBCL histologic subtype (B) (p 5 .0001). Abbreviations: DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B cell.
and the well-controlled treatment in a multicenter setting— although patients were treated outside a clinical trial, avoiding the known overestimation effects in pivotal trials [27]. Furthermore, unlike prospective trials published up to now [13, 21], we included only patients affected by R/R DLBCL. The main limitation of this study was the retrospective data assessment. An additional limitation was the lack of a central pathology review. However, all participating centers are experienced in lymphoma diagnosis and management, and expert hemopathologists were actively involved. In the present analysis, we provided evidence that lenalidomide administered as single agent achieves an ORR of 37% in R/R DLBCL patients. This result is in line with previously reported ORRs of 35% and 33% [14, 15]. The percentage of response varied significantly according to IHC subtype, namely 65% in non-GCB compared with 3% in GCB (p , .0001). In particular, 32% of non-GCB patients achieved CR versus none of the GCB group (p , .0001), and 33% versus 3% achieved PR (p , .001). These results seem more favorable with respect to the study of HernandezIlizaliturri et al. [22], who reported an ORR of 53% in non-GCB
with respect to 9% in GCB, probably because patients in the present analysis underwent fewer treatment lines. This suggests that lenalidomide may be more effective when used as an early therapeutic option. Nevertheless, we confirmed that the advantage of lenalidomide treatment in non-GCB with respect to GCB is likely caused by the inhibitory activity of this immunomodulatory drug on the NF-kB pathway, which is aberrant in non-GCB [28]. In the present analysis, the drug dose (25 vs. 15 mg/day) significantly influenced the ORR, namely 51% vs. 21% (p 5 .002), mirroring the preclinical data on dosedependent pharmacokinetics [29]. In contrast to our data, Zinzani et al. [26] observed a similar ORR between different lenalidomide dose levels (10, 15, and 25 mg/day); however, their study population included patients affected by different types of lymphoma and of higher median age. Lenalidomide was well tolerated in the present patient cohort of R/R DLBCL. In line with previous reports [13, 21, 26], lenalidomide toxicity consisted mainly of myelotoxicity. The most common adverse events were grade 3/4 neutropenia (24%) and thrombocytopenia (11%). Notably, the incidence of febrile neutropenia was low (3%) and manageable.
OTncologist he
©AlphaMed Press 2016
®
Mondello, Steiner, Willenbacher et al.
1111
Figure 2. Kaplan-Meier analysis of overall survival for all patients (A) and by DLBCL histologic subtype (B). Abbreviations: DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B cell; ns, not significant.
Furthermore, significant grade 3/4 nonhematologic toxicities were rare. Overall, the response duration was substantial, with a median of 9 months (range, 1–23), consistent with earlier findings [26]. Response duration was significantly influenced by lenalidomide dose (10 months with 25 mg vs. 4 months with 15 mg; p 5 .03) and IHC group (15 months in non-GCB vs. 4 months in GCB; p , .0001). Except for the differences regarding lenalidomide dosing, these data compare favorably with the data by Zinzani et al. [26]. Overall, the median PFS was 34 months, with a significantly longer duration in non-GCB patients than in GCB patients (37 vs. 30 months; p , .0001), which is in line with data reported by Hernandez-Ilizaliturri et al. [22]. However, although the number of responses, response duration, and PFS were significantly superior in the non-GCB group, no difference in OS was observed between the two subtypes (41 months vs. 38 months; p 5 .4).This confirms previously reported data [22, 26] but might be related to insufficient follow-up time.
CONCLUSION These data confirm that lenalidomide is an effective and well-tolerated treatment in clinical practice for R/R DLBCL. Lenalidomide proved to induce responses in both non-GCB
and GCB DLBCL, with a superior response rate and prolonged survival in non-GCB DLBCL. If clinically possible, we suggest the use of the 25 mg/day regimen and not 15 mg/day.
ACKNOWLEDGMENT This article did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
AUTHOR CONTRIBUTIONS Conception/Design: Patrizia Mondello, Michael Mian Provision of study material or patients: Patrizia Mondello, Wolfgang Willenbacher, Simone Ferrero, Vincenzo Pitini, Michael Mian Collection and/or assembly of data: Patrizia Mondello, Normann Steiner, Paola Ghione, Alessandra Marabese Data analysis and interpretation: Patrizia Mondello Manuscript writing: Patrizia Mondello Final approval of manuscript: Patrizia Mondello, Wolfgang Willenbacher, Simone Ferrero, Vincenzo Pitini, Salvatore Cuzzocrea, Michael Mian
DISCLOSURES Wolfgang Willenbacher: Celgene, Roche, Janssen, Takeda, CTI Life Sciences (C/A), Celgene, Gilead, Novartis, Roche (H), Oncotyrol, Celgene, Bristol-Myers Squibb (RF). The other authors indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ inventor/patent holder; (SAB) Scientific advisory board
REFERENCES 1. Al-Hamadani M, Habermann TM, Cerhan JR et al. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011. Am J Hematol 2015;90: 790–795. 2. Alizadeh AA, Eisen MB, Davis RE et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403: 503–511. 3. Lenz G, Wright GW, Emre NCT et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci USA 2008;105:13520–13525. 4. Rimsza LM, Leblanc ML, Unger JM et al. Gene expression predicts overall survival in paraffinembedded tissues of diffuse large B-cell lymphoma treated with R-CHOP. Blood 2008;112:3425–3433.
www.TheOncologist.com
5. Masuda N, Ohnishi T, Kawamoto S et al. Analysis of chemical modification of RNA from formalin-fixed samples and optimization of molecular biology applications for such samples. Nucleic Acids Res 1999;27:4436–4443.
9. Coutinho R, Clear AJ, Owen A et al. Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: Implications for therapeutic strategies. Clin Cancer Res 2013;19:6686–6695.
6. Hans CP, Weisenburger DD, Greiner TC et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103:275–282.
10. Rosenwald A,Wright G, Chan WC et al.The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937–1947.
7. Choi WWL,Weisenburger DD, Greiner TC et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 2009;15:5494–5502. 8. Meyer PN, Fu K, Greiner TC et al. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol 2011;29: 200–207.
11. Wright G, Tan B, Rosenwald A et al. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA 2003;100:9991–9996. 12. Lenz G, Wright G, Dave SS et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008;359:2313–2323. 13. Wiernik PH, Lossos IS, Tuscano JM et al. Lenalidomide monotherapy in relapsed or refractory
©AlphaMed Press 2016
1112
Lenalidomide in Relapsed/Refractory DLBCL
aggressive non-Hodgkin’s lymphoma. J Clin Oncol 2008;26:4952–4957.
severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 2005;11:5984–5992.
and beyond: Evolving concepts and practical applications. Blood 2011;117:5019–5032.
14. Witzig TE, Vose JM, Zinzani PL et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol 2011;22: 1622–1627.
19. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G et al. Immunomodulatory drugs stimulate natural killercell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the antitumour activity of rituximab in vivo. Br J Haematol 2008;140:36–45.
24. Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 1999;17:1244.
15. Wang M, Fowler N,Wagner-Bartak N et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: A phase II clinical trial. Leukemia 2013; 27:1902–1909.
20. Keifer JA, Guttridge DC, Ashburner BP et al. Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity. J Biol Chem 2001;276:22382–22387.
16. Mondello P, Pitini V, Barresi V et al. Extranodal diffuse large B-cell lymphoma with monoclonal gammopathy: An aggressive and primary refractory disease responding to an immunomodulatory agent. Exp Hematol Oncol 2016;5:1.
21. Habermann TM, Lossos IS, Justice G et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol 2009;145: 344–349.
17. Witzig TE, Nowakowski GS, Habermann TM et al. A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma. Ann Oncol 2015;26:1667–1677.
22. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL et al. Higher response to lenalidomide in R/R diffuse large B-cell lymphoma in nongerminal center B-celllike than in germinal center B-cell-like phenotype. Cancer 2011;117:5058–5066.
18. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B et al. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a
23. Campo E, Swerdlow SH, Harris NL et al. The 2008 WHO classification of lymphoid neoplasms
25. Cheson BD, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586. 26. Zinzani PL, Rigacci L, Cox MC et al. Lenalidomide monotherapy in heavily pretreated patients with non-Hodgkin lymphoma: An Italian observational multicenter retrospective study in daily clinical practice. Leuk Lymphoma 2015;56:1671–1676. 27. Singal AG, Higgins PDR,Waljee AK. A primer on effectiveness and efficacy trials. Clin Transl Gastroenterol 2014;5:e45. 28. Zhang L-H, Kosek J,Wang M et al. Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression. Br J Haematol 2013;160:487–502. 29. Rozewski DM, Herman SEM, Towns WH 2nd et al. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J 2012;14:872–882.
For Further Reading: Paul A. Hamlin, Sacha Satram-Hoang, Carolina Reyes et al. Treatment Patterns and Comparative Effectiveness in Elderly Diffuse Large B-Cell Lymphoma Patients: A Surveillance, Epidemiology, and End Results-Medicare Analysis. The Oncologist 2014;19:1249–1257. Implications for Practice: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that is curable with guideline-based chemoimmunotherapy; however, in real-world practice, very elderly patients are less likely to receive treatment. Evidence from this analysis suggests that chemoimmunotherapy effectiveness is generally similar between elderly patients in routine oncology practice and younger patients from clinical trial settings.This real-world comparative effectiveness study concludes that age alone should not discourage the use of guideline-recommended therapies for DLBCL, and in the absence of other reasons for withholding treatment, elderly patients should be given guideline-based treatment as often as nonelderly patients.
OTncologist he
©AlphaMed Press 2016
®
Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Is It a Valid Treatment Option? PATRIZIA MONDELLO,a,b,c NORMANN STEINER,d WOLFGANG WILLENBACHER,d SIMONE FERRERO,e PAOLA GHIONE,e ALESSANDRA MARABESE,f VINCENZO PITINI,a SALVATORE CUZZOCREA,b MICHAEL MIANd,f a Department of Human Pathology and bDepartment of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Messina, Italy; cLymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA; dInternal Medicine V, Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; eDivision of Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy; fDepartment of Hematology and Center for Bone Marrow Transplantation, Ospedale di Bolzano, Bolzano, Italy
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Diffuse large B-cell lymphoma x Lenalidomide x Immunomodulatory drug x Relapsed/refractory lymphoma
ABSTRACT Background. Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease. Prospective clinical trials have demonstrated that lenalidomide is an effective and safe treatment option, especially for non-germinal center B-cell (non-GCB) DLBCL. However, routine clinical data are lacking, which is why we provide the results of the so-far largest relapsed/refractory (R/R) DLBCL real-life analysis. Methods. We retrospectively assessed 123 R/R DLBCL patients who received either 15 or 25 mg/day of lenalidomide from January 2006 to January 2015. Results. During a median follow-up period of 4.5 years, complete remission was achieved in 32% and a partial remission in 33% non-GCB patients compared with 0% and 3% in the
GCB group (p , .001 and .001, respectively), with median response durations of 15 and 5 months, respectively (p , .001). Lenalidomide at 25 mg was superior to 15 mg in terms of response (complete remission 21% and partial remission 23% vs. 0% and 8%; p 5 .007 and .05) and median response duration (10 vs. 4 months; p 5 .03). Toxicity was limited and reversible. Median progression-free survival differed between non-GCB and GCB patients (37 vs. 30 months; p , .001) and between the two dosages (24 vs. 34 months; p 5 .002). However, overall survival was similar between the subgroups (38–42 months). Conclusion. We provide evidence that lenalidomide is a valid treatment option for R/R DLBCL, with limited and reversible toxicity, and is more efficient in non-GCB DLBCL and at higher doses. The Oncologist 2016;21:1107–1112
Implications for Practice: Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease; hence, novel therapeutic approaches are urgently needed. This study confirms that lenalidomide is a valid and well-tolerated treatment option for relapsed/refractory (R/R) DLBCL. Superior outcomes were observed in non-germinal center B-cell (GCB) DLBCL, probably because of inhibition of the nuclear factor-kB pathway. Similarly, high drug doses resulted in greater clinical benefits. Overall, lenalidomide is a suitable therapeutic option for R/R DLBCL, especially in nonGCB DLBCL, and 25 mg/day dosing should be preferred.
INTRODUCTION Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for approximately 30% of new cases of non-Hodgkin’s lymphoma (NHL) [1]. Despite its uniform morphology, DLBCL is a very heterogeneous disease at the molecular level. By gene expression profiling (GEP), DLBCL is classifiable into two main subgroups based on the cell of origin (COO), namely the germinal center B cell (GCB) and the activated B cell (ABC) [2, 3]. However, GEP is not routinely available because of the lack of standardized commercial
tests and the need for fresh frozen tissue samples. Although methodologies based on paraffin are currently under development [4], RNA extraction yields are low, and more importantly, the RNA obtained is heavily degraded and chemically modified [5]. Several attempts have been made to correlate the two subtypes with immunohistochemical (IHC) markers [6–8].The Hans algorithm is the most commonly used and distinguishes non-GCB and GCB patients [8]. Although these algorithms provide a practical method for
Correspondence: Patrizia Mondello, M.D., M.Sc., Lymphoma Department, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.Telephone: 917-353-5554; E-Mail: [email protected] Received March 12, 2016; accepted for publication April 5, 2016; published Online First on July 5, 2016. ©AlphaMed Press 1083-7159/2016/$20.00/0 http://dx.doi.org/10.1634/theoncologist.20160103
The Oncologist 2016;21:1107–1112 www.TheOncologist.com
©AlphaMed Press 2016
Lenalidomide in Relapsed/Refractory DLBCL
1108
designating subtypes, they are a suboptimal alternative to GEP [9]. COO subtypes are characterized by distinct oncogenic driver pathways, such as the dysregulation of nuclear factor (NF)-kB pathway in ABC, resulting in variable susceptibility to different antineoplastic drugs and variable prognoses [10, 11]. In particular, the cure rate of approximately 40% in ABC DLBCL after standard immunochemotherapy is significantly inferior to that of GCB [12]. Therefore, novel therapeutic approaches targeting these different pathways are urgently needed for such patients, especially those with relapsed/refractory (R/R) disease. Recently, lenalidomide, an immunomodulatory drug, has emerged as an attractive therapeutic option for patients with NHL, including ABC DLBCL [13–17]. Lenalidomide can stimulate the innate immune system, potentiate the antitumor activity of rituximab, and inhibit angiogenesis [18, 19]. These effects can be explained by the ability to inhibit tumor necrosis factor-a, vascular endothelial growth factor, and NF-kB in cancer cells [19, 20]. Two phase 2 trials, NHL-002 and NHL-003 [13, 21], reported an overall response rate (ORR) of approximately 28%, with complete response (CR) of 7%–12%, after lenalidomide monotherapy in R/R DLBCL. Responses were durable, with a median response duration of 4.6 months.The treatment was usually well tolerated. Grade 3/4 toxicity was mainly hematologic (neutropenia and thrombocytopenia) and reversible after lenalidomide dose reduction [13, 14]. Hernandez-Ilizaliturri et al. [22] demonstrated that lenalidomide was more effective in non-GCB-like than GCB-like DLBCL in the R/R setting. However, Wang et al. [15] did not observe any variation in clinical responses using the lenalidomiderituximab combination according to the COO. Up to now, there has been no large real-life analysis assessing the efficacy and toxicity of lenalidomide in R/R DLBCL. This is of major importance, because patients enrolled in clinical trials are often highly selected, and consequently their results do not reflect clinical practice. Therefore, we retrospectively assessed 123 consecutive R/R DLBCL patients treated with lenalidomide in three European cancer centers, with the aim of evaluating efficacy and toxicity in the whole group and in the main biological subgroups according to the COO by immunohistochemistry.
were based on physician’s choice. In the case of neutropenia, granulocyte-colony stimulating factors were used at the investigators’ discretion. Response to therapy was evaluated according to Cheson et al. [24, 25] and toxicity according to the Common Terminology Criteria for Adverse Events v4.0 (http:// ctep.cancer.gov/protocolDevelopment/electronic_applications/ ctc.htm). Treatment response was assessed approximately 3 months after start of treatment by a full physical examination, blood tests, and bone marrow aspirate and biopsy in case of bone marrow involvement at diagnosis. Eighty-seven patients (71%) underwent imaging studies (computed tomography).
Statistical Analyses The x 2 test was performed to assess the significance of differences between categorical variables. Overall survival (OS), progression-free survival (PFS), and disease-free survival were defined according to Cheson et al. [24] and were plotted as curves using the Kaplan-Meier method [23]. The log-rank test was used to assess the impact of categorical variables on survival. Statistical analyses were performed with MedCalc (version 11.0; MedCalc Software, Ostend, Belgium, http:// www.medcalc.org) and GraphPad Prism (version 5.0; GraphPad, San Diego, CA, http://www.graphpad.com). The limit of significance for all analyses was defined as p , .05.
RESULTS Patient Characteristics at Start of Treatment Fifty-seven patients (46%) had GCB DLBCL, and the remaining 66 (54%) were classified into the non-GCB group. Clinical features are summarized in Table 1 and were similar between patients with GCB and non-GCB (data not shown). Overall, the median age at time of diagnosis was 64 years (range, 29–85). A male predominance was observed (75/123, 61%). Most patients had stage III or IV disease (101/123, 82%), B symptoms (75/123, 61%), bone marrow involvement (63/123, 51%), elevated lactate dehydrogenase (81/123, 66%), and elevated b2-microglobulin (66/123, 54%). Only a minority (n 5 30, 24%) had bulky disease, defined as a tumor mass of $5 cm. All patients underwent at least 1 treatment line (range 1–3), and 19% underwent autologous stem cell transplantation.
Treatment and Response METHODS Patients We retrospectively assessed 123 consecutive patients affected by R/R DLBCL in three cancer centers, two Italian and one Austrian, from January 2006 to January 2015. Histologic diagnosis was performed according to World Health Organization criteria by an expert pathologist at each participating center [23]. All patients $18 years or older with R/R DLBCL, regardless of disease stage, were included. This analysis was approved by the local ethics committees.
Treatment Plan Patients received a starting dose of either 15 or 25 mg/day of lenalidomide for 21 days of a 28-day cycle until disease progression or relapse.The initial dosing and dose adjustments
Overall, 909 cycles were administered to 123 patients, with 24 (20%) patients receiving 15 mg/day (GCB, n 5 13; non-GCB, n 5 11) and 99 (80%) patients receiving 25 mg/day (GCB, n 5 44; non-GCB, n 5 55). ORR was 37%, CR 21%, and partial remission (PR) 24%. Response to therapy was observed mainly in the patients who had at least stable disease with previous treatments compared with refractory disease (CR 22% vs. 0%, p 5 .007; PR 23% vs. 7%, p 5 .05). Progressive disease was similar between these two groups of patients (52% vs. 67%, p 5 .18). ORR differed significantly between the two IHC subtypes and was higher in non-GCB than GCB (65% vs. 3%; p , .0001) (Table 2). More patients with non-GCB achieved a CR or PR (32% and 33%, respectively) than patients with GCB (0% and 3%, respectively; p , .0001 and p 5 .001, respectively). The median response time was 5 months (range, 4–7) in the GCB group and 2 months (range, 2–3) in the non-GCB group (p 5 .02). Similarly, ORR varied according to lenalidomide dose and
OTncologist he
©AlphaMed Press 2016
®
Mondello, Steiner, Willenbacher et al.
1109
Table 1. Patient characteristics (n 5 123). Parameter Age, years Median .60 Sex Female Male IHC lymphoma subtype GCB Non-GCB B symptoms Bone marrow involvement Bulky disease .2 extranodal sites Elevated lactate dehydrogenase Elevated b2-microglobulin Ki-67 .30% Stage I II III IV Baseline performance status .1 IPI prognostic group Low risk (0–1 risk factors) Low-intermediate risk (2 risk factors) High-intermediate risk (3 risk factors) High risk (4–5 risk factors) Median time from diagnosis to first dose of lenalidomide, months (range) Median number of treatment regimens (range) Prior radiotherapy Prior autologous stem cell transplantation
Value 64 87 (71) 48 (39) 75 (61) 57 (46) 66 (54) 75 (61) 63 (51) 30 (24) 51 (41) 81 (66) 66 (54) 84 (69) 3 (2) 19 (15) 23 (19) 78 (64) 21 (17) 6 (5) 24 (20) 51 (41) 42 (34) 23 (3–92) 1 (1–3) 60 (49) 23 (19)
Data are presented as n (%) unless noted otherwise. Abbreviations: GCB, germinal center B cell; IHC, immunohistochemical; IPI, International Prognostic Index.
was higher in patients receiving 25 mg/day than in those receiving 15 mg/day (44% vs. 8%; p 5 .002). The CR rate for patients receiving 25 mg/day was 21% versus 0% for 15 mg/day (p 5 .007), and the PR rate was 23% versus 8% (p 5 .05). The median response time was 3 months (range, 2–6) in those who received 25 mg/day and 4 months (range, 3–7) in those who received 15 mg/day (not significant). Lenalidomide was well tolerated. The most common adverse event of any grade and cause was reversible myelosuppression. Grade 1/2 hematologic toxicity consisted mainly of anemia (n 5 22, 18%) followed by neutropenia (n 5 7, 6%) and thrombocytopenia (n 5 7, 6%). Hematologic grade 3/4 toxicity consisted of neutropenia (n 5 29, 24%) and thrombocytopenia (n 5 13, 11%); grade 3/4 anemia did not occur. Myeloid growth factors were administered to 22 patients (18%). Grade 3/4 febrile neutropenia occurred in only 4 patients (3%). Grade 3/4 nonhematologic events were
www.TheOncologist.com
uncommon, consisting of elevated transaminases (n 5 2, 2%) and neuropathy (n 5 1, 1%). In contrast, nonhematologic adverse events of grade 1/2 were more commonly observed. In particular, almost half of the cohort experienced peripheral neuropathy (n 5 64, 52%) and fatigue (n 5 53, 43%). Toxicity was reversible in all cases. Eight patients receiving 25 mg/day lenalidomide (8%) required dose reduction (n 5 6, 6%) or treatment interruption because of toxicity (n 5 2, 2%). The median time to first dose reduction or treatment interruption was 9 weeks, corresponding to the third treatment cycle (range, 1–5 cycles). Among the 6 patients who required dose reduction, 2 required only 1 reduction (to 20 mg) and 4 had 2 dose reductions (to 15 mg). The most common reasons for dose reduction were neutropenia (83%) and thrombocytopenia (17%). Treatment interruptions were typically brief, lasting a median of 9 days (range, 6–16 days).
Follow-Up The median follow-up was 4.5 years (range, 2–108 months). In the whole cohort, progressive disease (PD) during lenalidomide treatment occurred in 68 patients (55%). Fifty-one patients (90%) of the GCB group experienced PD compared with 17 (26%) in the non-GCB group (p , .0001). PD also varied according to lenalidomide dose: 19 patients (79%) who received 15 mg/day had PD, whereas 44 (49%) who received 25 mg/day (p 5 .02) had PD. The overall median duration of response, defined as time from maximum response until PD, was 9 months (range, 1–23 months), 5 months (range, 1–10) in the GCB group and 15 months (range, 5–23) in the non-GCB group (p , .0001). The median duration of CR, calculable only for patients with non-GCB DLBCL who received 25 mg/day lenalidomide, was 14 months (range, 5–23). Duration of remission also depended on lenalidomide dose and was 4 months (range, 1–9) in the 15-mg group and 10 months (range, 2–23) in the 25-mg group (p 5 .03). Overall, the median PFS was 34 months (range, 2–108), 37 months (range, 9–108) in the non-GCB group and 30 months (range, 2–74) in the GCB group (p , .0001) (Fig. 1). Similarly, patients in the 25-mg group achieved a longer median PFS of 34 months (range, 5–108) versus 24 months (range, 2–54; p 5 .002) in the 15-mg group. However, OS did not differ significantly between the subgroups (38 vs. 41 months in nonGCB and GCB, respectively, p 5 .2; 38 vs. 42 months in 15- and 25-mg groups) (Fig. 2).
DISCUSSION Up to now, the safety and efficacy of single-agent lenalidomide for the treatment of hematologic malignancies have been investigated intensively in many prospective clinical trials [13–15, 21]. Although it has emerged as a valid treatment option in these selected patient cohorts, live data are lacking. Therefore, we retrospectively assessed the so-far largest R/R DLBCL cohort to undergo lenalidomide monotherapy in clinical practice. Herein, we provide evidence that lenalidomide is a safe and effective treatment option for this patient setting. However, the best responses were observed in the non-GCB group and those who received 25 mg/day. The strengths of this analysis were the relatively long follow-up (nearly twice that of previous reports) [13, 22, 26] ©AlphaMed Press 2016
Lenalidomide in Relapsed/Refractory DLBCL
1110
Table 2. Best overall response by lenalidomide dose and IHC lymphoma subtype. Lenalidomide dose
IHC lymphoma subtype
Best overall response
15 mg/day
25 mg/day
GCB
Non-GCB
Overall
n Overall response Complete response Partial response Stable disease Progression of disease Previous therapeutic line(s) Time to response, months Duration of response, months Disease-free survival, months Progression-free survival, months Overall survival, months
24 2 (8) 0 (0) 2 (8) 3 (13) 19 (79) 1 (1–2) 4 (3–7) 4 (1–9) 0 (0) 24 (2–54) 38 (7–81)
99 44 (44) 21 (21) 22 (23) 7 (7) 44 (49) 2 (2–5) 3 (2–6) 10 (2–23) 14 (5–23) 34 (5–108) 42 (10–127)
57 2 (3) 0 (0) 2 (3) 4 (7) 51 (90) 2 (1–5) 5 (4–7) 5 (1–10) 0 (0) 30 (2–74) 41 (18–68)
66 44 (65) 21 (32) 22 (33) 6 (9) 17 (26) 2 (0–3) 2 (2–3) 15 (5–23) 14 (5–23) 37 (9–108) 38 (7–127)
123 46 (37) 21 (17) 24 (20) 10 (8) 68 (55) 2 (0–5) 4 (2–7) 9 (1–23) 14 (5–23) 34 (2–108) 37 (7–127)
Data are presented as n (%) or mean (range). Abbreviations: GCB, germinal center B cell; IHC, immunohistochemical.
Figure 1. Kaplan-Meier analysis of progression-free survival for all patients (A) and by DLBCL histologic subtype (B) (p 5 .0001). Abbreviations: DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B cell.
and the well-controlled treatment in a multicenter setting— although patients were treated outside a clinical trial, avoiding the known overestimation effects in pivotal trials [27]. Furthermore, unlike prospective trials published up to now [13, 21], we included only patients affected by R/R DLBCL. The main limitation of this study was the retrospective data assessment. An additional limitation was the lack of a central pathology review. However, all participating centers are experienced in lymphoma diagnosis and management, and expert hemopathologists were actively involved. In the present analysis, we provided evidence that lenalidomide administered as single agent achieves an ORR of 37% in R/R DLBCL patients. This result is in line with previously reported ORRs of 35% and 33% [14, 15]. The percentage of response varied significantly according to IHC subtype, namely 65% in non-GCB compared with 3% in GCB (p , .0001). In particular, 32% of non-GCB patients achieved CR versus none of the GCB group (p , .0001), and 33% versus 3% achieved PR (p , .001). These results seem more favorable with respect to the study of HernandezIlizaliturri et al. [22], who reported an ORR of 53% in non-GCB
with respect to 9% in GCB, probably because patients in the present analysis underwent fewer treatment lines. This suggests that lenalidomide may be more effective when used as an early therapeutic option. Nevertheless, we confirmed that the advantage of lenalidomide treatment in non-GCB with respect to GCB is likely caused by the inhibitory activity of this immunomodulatory drug on the NF-kB pathway, which is aberrant in non-GCB [28]. In the present analysis, the drug dose (25 vs. 15 mg/day) significantly influenced the ORR, namely 51% vs. 21% (p 5 .002), mirroring the preclinical data on dosedependent pharmacokinetics [29]. In contrast to our data, Zinzani et al. [26] observed a similar ORR between different lenalidomide dose levels (10, 15, and 25 mg/day); however, their study population included patients affected by different types of lymphoma and of higher median age. Lenalidomide was well tolerated in the present patient cohort of R/R DLBCL. In line with previous reports [13, 21, 26], lenalidomide toxicity consisted mainly of myelotoxicity. The most common adverse events were grade 3/4 neutropenia (24%) and thrombocytopenia (11%). Notably, the incidence of febrile neutropenia was low (3%) and manageable.
OTncologist he
©AlphaMed Press 2016
®
Mondello, Steiner, Willenbacher et al.
1111
Figure 2. Kaplan-Meier analysis of overall survival for all patients (A) and by DLBCL histologic subtype (B). Abbreviations: DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B cell; ns, not significant.
Furthermore, significant grade 3/4 nonhematologic toxicities were rare. Overall, the response duration was substantial, with a median of 9 months (range, 1–23), consistent with earlier findings [26]. Response duration was significantly influenced by lenalidomide dose (10 months with 25 mg vs. 4 months with 15 mg; p 5 .03) and IHC group (15 months in non-GCB vs. 4 months in GCB; p , .0001). Except for the differences regarding lenalidomide dosing, these data compare favorably with the data by Zinzani et al. [26]. Overall, the median PFS was 34 months, with a significantly longer duration in non-GCB patients than in GCB patients (37 vs. 30 months; p , .0001), which is in line with data reported by Hernandez-Ilizaliturri et al. [22]. However, although the number of responses, response duration, and PFS were significantly superior in the non-GCB group, no difference in OS was observed between the two subtypes (41 months vs. 38 months; p 5 .4).This confirms previously reported data [22, 26] but might be related to insufficient follow-up time.
CONCLUSION These data confirm that lenalidomide is an effective and well-tolerated treatment in clinical practice for R/R DLBCL. Lenalidomide proved to induce responses in both non-GCB
and GCB DLBCL, with a superior response rate and prolonged survival in non-GCB DLBCL. If clinically possible, we suggest the use of the 25 mg/day regimen and not 15 mg/day.
ACKNOWLEDGMENT This article did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
AUTHOR CONTRIBUTIONS Conception/Design: Patrizia Mondello, Michael Mian Provision of study material or patients: Patrizia Mondello, Wolfgang Willenbacher, Simone Ferrero, Vincenzo Pitini, Michael Mian Collection and/or assembly of data: Patrizia Mondello, Normann Steiner, Paola Ghione, Alessandra Marabese Data analysis and interpretation: Patrizia Mondello Manuscript writing: Patrizia Mondello Final approval of manuscript: Patrizia Mondello, Wolfgang Willenbacher, Simone Ferrero, Vincenzo Pitini, Salvatore Cuzzocrea, Michael Mian
DISCLOSURES Wolfgang Willenbacher: Celgene, Roche, Janssen, Takeda, CTI Life Sciences (C/A), Celgene, Gilead, Novartis, Roche (H), Oncotyrol, Celgene, Bristol-Myers Squibb (RF). The other authors indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ inventor/patent holder; (SAB) Scientific advisory board
REFERENCES 1. Al-Hamadani M, Habermann TM, Cerhan JR et al. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011. Am J Hematol 2015;90: 790–795. 2. Alizadeh AA, Eisen MB, Davis RE et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403: 503–511. 3. Lenz G, Wright GW, Emre NCT et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci USA 2008;105:13520–13525. 4. Rimsza LM, Leblanc ML, Unger JM et al. Gene expression predicts overall survival in paraffinembedded tissues of diffuse large B-cell lymphoma treated with R-CHOP. Blood 2008;112:3425–3433.
www.TheOncologist.com
5. Masuda N, Ohnishi T, Kawamoto S et al. Analysis of chemical modification of RNA from formalin-fixed samples and optimization of molecular biology applications for such samples. Nucleic Acids Res 1999;27:4436–4443.
9. Coutinho R, Clear AJ, Owen A et al. Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: Implications for therapeutic strategies. Clin Cancer Res 2013;19:6686–6695.
6. Hans CP, Weisenburger DD, Greiner TC et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103:275–282.
10. Rosenwald A,Wright G, Chan WC et al.The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937–1947.
7. Choi WWL,Weisenburger DD, Greiner TC et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 2009;15:5494–5502. 8. Meyer PN, Fu K, Greiner TC et al. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol 2011;29: 200–207.
11. Wright G, Tan B, Rosenwald A et al. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA 2003;100:9991–9996. 12. Lenz G, Wright G, Dave SS et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008;359:2313–2323. 13. Wiernik PH, Lossos IS, Tuscano JM et al. Lenalidomide monotherapy in relapsed or refractory
©AlphaMed Press 2016
1112
Lenalidomide in Relapsed/Refractory DLBCL
aggressive non-Hodgkin’s lymphoma. J Clin Oncol 2008;26:4952–4957.
severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 2005;11:5984–5992.
and beyond: Evolving concepts and practical applications. Blood 2011;117:5019–5032.
14. Witzig TE, Vose JM, Zinzani PL et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol 2011;22: 1622–1627.
19. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G et al. Immunomodulatory drugs stimulate natural killercell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the antitumour activity of rituximab in vivo. Br J Haematol 2008;140:36–45.
24. Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 1999;17:1244.
15. Wang M, Fowler N,Wagner-Bartak N et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: A phase II clinical trial. Leukemia 2013; 27:1902–1909.
20. Keifer JA, Guttridge DC, Ashburner BP et al. Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity. J Biol Chem 2001;276:22382–22387.
16. Mondello P, Pitini V, Barresi V et al. Extranodal diffuse large B-cell lymphoma with monoclonal gammopathy: An aggressive and primary refractory disease responding to an immunomodulatory agent. Exp Hematol Oncol 2016;5:1.
21. Habermann TM, Lossos IS, Justice G et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol 2009;145: 344–349.
17. Witzig TE, Nowakowski GS, Habermann TM et al. A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma. Ann Oncol 2015;26:1667–1677.
22. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL et al. Higher response to lenalidomide in R/R diffuse large B-cell lymphoma in nongerminal center B-celllike than in germinal center B-cell-like phenotype. Cancer 2011;117:5058–5066.
18. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B et al. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a
23. Campo E, Swerdlow SH, Harris NL et al. The 2008 WHO classification of lymphoid neoplasms
25. Cheson BD, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586. 26. Zinzani PL, Rigacci L, Cox MC et al. Lenalidomide monotherapy in heavily pretreated patients with non-Hodgkin lymphoma: An Italian observational multicenter retrospective study in daily clinical practice. Leuk Lymphoma 2015;56:1671–1676. 27. Singal AG, Higgins PDR,Waljee AK. A primer on effectiveness and efficacy trials. Clin Transl Gastroenterol 2014;5:e45. 28. Zhang L-H, Kosek J,Wang M et al. Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression. Br J Haematol 2013;160:487–502. 29. Rozewski DM, Herman SEM, Towns WH 2nd et al. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J 2012;14:872–882.
For Further Reading: Paul A. Hamlin, Sacha Satram-Hoang, Carolina Reyes et al. Treatment Patterns and Comparative Effectiveness in Elderly Diffuse Large B-Cell Lymphoma Patients: A Surveillance, Epidemiology, and End Results-Medicare Analysis. The Oncologist 2014;19:1249–1257. Implications for Practice: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that is curable with guideline-based chemoimmunotherapy; however, in real-world practice, very elderly patients are less likely to receive treatment. Evidence from this analysis suggests that chemoimmunotherapy effectiveness is generally similar between elderly patients in routine oncology practice and younger patients from clinical trial settings.This real-world comparative effectiveness study concludes that age alone should not discourage the use of guideline-recommended therapies for DLBCL, and in the absence of other reasons for withholding treatment, elderly patients should be given guideline-based treatment as often as nonelderly patients.
OTncologist he
©AlphaMed Press 2016
®
