NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Non-Hodgkin’s lymphomas (NHLs) represent a highly heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer (NK) cells. B-cell lymphomas constitute approximately 80% of NHL cases, with 15% to 20% being of T-cell origin; NK cell lymphomas are rare.1 In the United States alone, 70,130 new cases of NHL and 18,940 deaths from the disease are estimated in 2012; cases of chronic lymphocytic leukemia are estimated separately, as discussed later.2 NHL is the seventh leading site of new cancer cases among men and women, accounting for 4% of new cancer cases and 3% of cancer-related deaths.2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NHLs are developed and updated as a result of annual meetings convened by a multidisciplinary panel of NHL experts, with the goal of providing recommendations on the standard practices for diagnostic workup, treatment, and surveillance strategies based on the current evidence. These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Guidelines for NHL and describe the clinical data supporting the recommendations made by the NCCN NHL Panel. The updates discussed in this article include recommendations on treatment regimens for chronic lymphocytic leukemia (CLL), surveillance imaging for the follow-up of patients with NHL, and first-line consolidation options for mantle cell lymphoma.
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
CLL
CLL remains the most commonly diagnosed leukemia among adults in the United States, with approximately 16,000 new cases estimated for 2012.2 The median age at diagnosis is 72 years, with approximately 70% of patients diagnosed at older than 65 years (and 40% diagnosed at age ≥75 years).3 Thus, CLL mainly affects “elderly” adults, which poses important challenges regarding the treatment approach in this population. Although chemoimmunotherapy with fludarabine, rituximab, and cyclophosphamide (FCR) represents the standard of care in younger or “fit” patients with CLL,4,5 older patients frequently present with comorbid conditions, which may decrease their ability to tolerate myelosuppressive regimens.6 In a phase III randomized trial conducted by the German CLL Study Group (GCLLSG), elderly patients (age >65 years; median age 70 years) were randomized to first-line treatment with fludarabine or chlorambucil (N=193).7 Fludarabine, compared with chlorambucil, resulted in significantly improved overall response rates (ORR; 72% vs. 51%), complete response (CR; 7% vs. 0%), and median time to treatment failure (18 vs. 11 months). However, no advantage with fludarabine was observed for median progression-free survival (PFS; 19 vs. 18 months) or overall survival (OS; 46 vs. 64 months).7 This study suggested that in older patients (or in patients with comorbidities) with CLL for whom more intensive regimens are not appropriate, chlorambucil remains a valid treatment option.
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
Two recent phase II studies reported outcomes with the combination of rituximab and chlorambucil as first-line treatment in patients with CLL, including in elderly patients.8–10 In the multicenter Italian study, elderly patients (age >60 years; median age 70 years; N=85 evaluable) received induction therapy with chlorambucil combined with rituximab (up to 8 cycles).8 Although responders were subsequently randomized to receive rituximab maintenance (every 2 months for 2 years) or observation, only data regarding induction therapy are currently available.8 After induction, the ORR was 81%, with CR (confirmed by CT scan) in 16.5% of patients; response rates were similar across Binet stages and age subgroups.8,9 The regimen was well tolerated, with treatment-related serious adverse events reported in 7 patients (8%).8 The multicenter phase II study from the United Kingdom (N=100) reported similar response outcomes and a favorable safety profile with chlorambucil combined with rituximab in previously untreated patients (median age 70 years; range, 43–86 years); the ORR and CR rates were 80% and 12%, respectively.10 Median PFS in this study was approximately 24 months. An ongoing randomized phase III study is evaluating first-line therapy with chlorambucil combined with rituximab versus chlorambucil alone (CLL11 study).
Bendamustine is an alkylating agent with a benzimidazole ring component, and exhibits low or incomplete cross-resistance with other alkylating agents.11,12 The activity of bendamustine compared with chlorambucil in patients with previously untreated CLL was established in a pivotal phase III randomized study (N=319).13–15 After a median observation time of 54 months, the median PFS was significantly longer with bendamustine (21 vs. 9 months; P<.0001).14,15 The higher response rates and PFS benefit with bendamustine were retained in the subgroup of older patients (age >65 years) on this trial.16 No differences in OS outcomes were observed between the treatment groups.15 Bendamustine is also being evaluated as part of a chemoimmunotherapy regimen in patients with CLL. In a multicenter phase II study from the GCLLSG, bendamustine in combination with rituximab (BR) showed high response rates (ORR 88%; CR 23%) in previously untreated patients, with similar response and survival outcomes among the subgroup of elderly patients (age >70 years).17 After a median observation time of 27 months, the median PFS for all patients was 34 months. However, the BR regimen seemed to have limited activity in patients with del(17p). In the small subgroup of patients with del(17p) (n=8), the ORR (all partial remissions) was 37.5% and median PFS was only 8 months.17 An ongoing phase III randomized trial is comparing outcomes between chemoimmunotherapy with FCR and BR in “fit” patients with previously untreated CLL (CLL10 study). The BR regimen was also active (ORR, 59%; CR, 9%) in patients with relapsed/refractory disease (N= 78) in a separate phase II study from the GCLLSG.18 The median PFS and OS in this study were 15 and 34 months, respectively. Similar outcomes were observed in the subgroup of elderly patients (age >70 years). Patients with del(17p) (n=14) had poorer outcomes with treatment; the ORR in this subgroup was 7% (1 CR) and the median PFS and OS were 7 and 16 months, respectively.18
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Recommendations
The NCCN NHL Panel recommended changing chlorambucil with or without prednisone to chlorambucil with or without rituximab as one of the preferred treatment options listed for the following patient subgroups with CLL: first-line regimen for patients who are frail or have significant comorbidities; and first-line or relapsed/refractory treatment for patients without del(17p) or those with del(11q) [but without del(17p)], who are aged 70 years or older or who are younger with comorbidities (see CSLL-D 1 of 5 and CSLL-D 3 of 5, pages 1488 and 1490, respectively). This recommendation was based on available data (discussed earlier) from multicenter phase II studies with chlorambucil combined with rituximab in first-line CLL (including in elderly patients), and the phase III randomized study in elderly patients that showed no advantage with first-line fludarabine over chlorambucil monotherapy. For the subgroup of poor-risk patients with del(17p), the panel recommended removing bendamustine with or without rituximab from the first-line and relapsed/refractory treatment options (see CSLL-D 2 of 5, page 1489) in light of data from multicenter phase II studies that showed limited activity of the BR regimen in subgroups with del(17p).
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
Surveillance Imaging in NHL
Imaging studies using modalities such as CT or PET/CT scans are important components of diagnostic workup, interim restaging, and posttreatment assessments in patients with lymphomas. Although functional imaging studies are now considered a standard part of posttreatment response evaluation in patients with aggressive NHL and Hodgkin lymphoma, their role in indolent lymphomas or for routine surveillance during longer-term follow-up of patients with NHL remains to be clarified by additional data.
Follicular Lymphoma
Only a few studies have evaluated the role of follow-up surveillance imaging for detecting relapse in patients with indolent NHL. In an early retrospective study, patients with stage I–III follicular lymphoma (FL) with a CR after induction were evaluated with clinical, laboratory, and imaging studies during routine follow-up (N=257).19 Patients underwent CT scans of the abdomen and/or pelvis during follow-up visits. Follow-up was typically performed every 3 to 6 months for the first 5 years of treatment, and then annually thereafter. The median follow-up time was 80 months (range, 13–209 months). Among the patients included in this analysis, relapse was detected in 78; most relapses (77%) occurred within the first 5 years of treatment.19 Eleven of the relapses were detected with abdominal and/or pelvic CT scans alone. In this analysis, 4% of patients with an initial CR had recurrence determined by routine surveillance with CT scans.19
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
A recent prospective study evaluated the role of surveillance PET scans in patients with lymphomas (Hodgkin lymphoma and NHL) with a CR after induction.20 PET scans were performed every 6 months for the first 2 years after completion of induction, then annually thereafter. In the cohort of patients with indolent NHL (n=78), follow-up PET scans detected true relapses in 10% of patients at 6 months (8 of 78), 12% at 12 months (8 of 68), 9% at 18 months (5 of 56), 9% at 24 months (4 of 47), 8% at 36 months (3 of 40), and 6% at 48 months (2 of 34).20 Among 13 patients who had PET-positive findings without a corresponding abnormality on CT scan, relapse was documented in 8 of these cases by biopsy. Notably, of the 47 PET-positive relapses, 38 were detected on CT scan and 30 were detected clinically at the same time as PET. Whether this earlier detection of relapse in a proportion of patients translates to improved outcomes is unclear.
Diffuse Large B-Cell Lymphoma
Considerable debate remains in the routine use of follow-up imaging for surveillance in patients with diffuse large B-cell lymphoma (DLBCL) who achieve a CR after induction therapy. Although positive imaging scans can help identify patients with early asymptomatic relapse, false-positivity remains common. This is problematic when it leads to unnecessary radiation exposure for patients and increased health care costs. In a study that evaluated the use of surveillance CT scans (at 3 and 12 months after completion of therapy) in patients with DLBCL who achieved a CR with induction chemotherapy (N=117), 35 experienced relapse, and only 6% of these relapses were detected on follow-up CT scan in asymptomatic patients; 86% of cases of relapse were associated with development of new symptoms or signs of relapse.21 The investigators therefore concluded that routine surveillance with CT scans had limited value in the detection of early relapse in patients with a CR after induction. In a retrospective study that evaluated the use of surveillance imaging in patients with relapsed aggressive lymphoma who experienced a CR to initial chemotherapy (N=108), 20% of relapses were detected by imaging in asymptomatic patients.22 In the remaining 80% of cases, relapse was identified by clinical signs and/or symptoms. The cases of relapse detected on imaging were more likely to represent a population of patients with low-risk disease based on age-adjusted International Prognostic Index at relapse.22 Thus, routine imaging during remission seemed to help identify patients with more limited disease at relapse, which had a nonsignificant trend showing improved outcome. In the prospective study mentioned earlier,20 the role of PET scans was also evaluated in patients with aggressive NHL who experienced a CR after induction (n=183). In this cohort of patients with aggressive lymphomas, follow-up PET scans detected true relapses in 10% of patients at 6 months (19 of 183), 5% at 12 months (8 of 163), 11% at 18 months (16 of 152), 2% at 24 months (3 of 134), 1% at 36 months (1 of 130), and 1% at 48 months (1 of 129).20 Of the 56 PET-positive relapses, 45 were detected on CT scan and 40 were detected clinically at the same time as the PET scan. Again, the value of early detection of relapse was not demonstrated by improved outcomes.20 In another recent study, the use of follow-up PET/CT scan was retrospectively evaluated in patients with DLBCL who experienced a CR after induction (N=75).23 Follow-up PET/CT scans detected 27 cases of relapse, of which 23 were confirmed as relapses based on biopsy evaluation; thus, the positive predictive value of PET/CT scan for detecting relapse in this study was 0.85. Among 35 asymptomatic patients with surveillance PET scans, 4 had positive scans and recurrence was confirmed in 3.23 Thus, the clinical utility of surveillance PET scans in asymptomatic patients was limited in this study.
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Guidelines Insights: Non-Hodgkin’s Lymphomas, Version 3.2012
Version 3.2012 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 12; 10.6004/jnccn.2012.0155
NCCN Recommendations
In the absence of evidence showing improved survival outcomes with early PET detection of relapse, PET scans are not recommended for routine surveillance of FL or DLBCL in patients who have achieved a CR after treatment. However, results of several studies suggest that surveillance imaging with CT may identify early asymptomatic relapse. However, it has not been clearly established that this early detection is associated with a superior long-term outcome. To minimize the potential risks associated with ongoing surveillance imaging (ie, unnecessary biopsies or radiation exposure), the NCCN NHL Panel recommended follow-up surveillance imaging with CT scans no more than once every 6 months for up to 2 years after completion of therapy for patients with FL in remission, and no more than once yearly thereafter unless clinically indicated (see FOLL-2, page 1491). For patients with DLBCL in remission, the panel recommended follow-up surveillance imaging with CT scans no more than once every 6 months for up to 2 years (after completion of therapy), with no ongoing routine surveillance imaging after that time unless prompted by clinical signs or symptoms (see BCEL-4 and BCEL-5, pages 1492 and 1493). For patients with symptoms or clinical findings, imaging is appropriate to evaluate for potential disease recurrence and evaluate extent of disease.
Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is a less common subtype of NHL, constituting approximately 6% of cases.1 MCL generally follows an aggressive disease course and remains incurable with current therapies. The standard of care for initial treatment of MCL is not well defined. Several regimens have shown significant activity in patients with newly diagnosed MCL, but none of these regimens are curative in patients with advanced disease. In general, rituximab used in combination with aggressive chemotherapy regimens has resulted in favorable PFS and OS outcomes.24–27 For patients who are physically fit, consolidation with high-dose therapy and autologous stem cell rescue (HDT/ASCR) after remission-induction therapy (usually with an intensive rituximab-containing regimen) may offer the best chance for longer-term remission.25,26,28,29 In the Nordic MCL trial, induction therapy with rituximab and dose-intensified CHOP (maxi-CHOP) alternating with high-dose cytarabine resulted in an ORR and CR rate of 96% and 54%, respectively, in previously untreated patients (age ≤65 years) with MCL (N=160).25 Responding patients were eligible to proceed with HDT/ASCR. The 6-year PFS and OS rates were 66% and 70%, respectively, with no relapses occurring after 5 years.25 A recently published analysis from the NCCN Oncology Outcomes Database reported superior PFS outcomes with R-hyper-CVAD alone or with rituximab-containing regimens followed by HDT/ASCR, compared with R-CHOP alone, in the first-line setting for younger patients (age <65 years) with MCL.30
Not all patients with MCL are physically fit or eligible to undergo aggressive first-line treatment regimens and HDT/ASCR. For patients who are older or otherwise not candidates for HDT/ASCR, postremission maintenance with rituximab may prolong remission duration.31–34 An early study with rituximab maintenance after a modified (less intensive) R-hyper-CVAD regimen seemed to show PFS benefit.32 More recently, the European MCL Network conducted a phase III randomized trial in older patients (age >60 years not eligible for HDT/ASCR) with previously untreated MCL (N=560; n=485 evaluable for response) to evaluate induction with R-FC (rituximab, fludarabine, cyclophosphamide) versus R-CHOP, with a second randomization to maintenance with rituximab versus interferon alfa (given until progression occurred in both arms).34 Response after induction therapy with R-CHOP and R-FC was similar (CR/unconfirmed CR rate, 49% vs. 53%; ORR, 86% vs. 78%, respectively), but more patients experienced progression during R-FC than with R-CHOP (14% vs. 5%). The median duration of response was similar between R-CHOP and R-FC (36 vs. 37 months). After a median follow-up of 36 months, OS (from time of first randomization) was significantly longer with R-CHOP compared with R-FC (median, 67 vs. 40 months; 4-year OS rate, 62% vs. 47%; P=.005) in the intent-to-treat analysis.34 Grade 3/4 hematologic toxicities occurred more frequently with R-FC induction. Among the patients who responded to induction and underwent second randomization (n=316), remission duration (from time of second randomization) was significantly improved with rituximab maintenance compared with interferon alfa (median, 75 vs. 27 months; 4-year rate, 57% vs. 34%; P<.001). Survival outcomes (from time of first randomization) were not significantly different between maintenance with rituximab and interferon alfa (4-year OS rate, 79% vs. 67%) after a median follow-up of 42 months. However, in the subgroup of patients treated with R-CHOP induction (n=174), OS was significantly longer with rituximab maintenance compared with interferon alfa (median not reached vs. 64 months; 4-year OS rate, 87% vs. 63%; P=.005).34 Results from this study suggests that for patients who are not eligible for HDT/ASCR as part of first-line therapy, R-CHOP induction followed by rituximab maintenance may offer the best chance to prolong remission duration. Given the positive outcomes reported in this study (with median duration of response exceeding 6 years with rituximab maintenance and a 4-year OS rate of 87% in patients treated with R-CHOP and rituximab maintenance), whether first-line consolidation with HDT/ASCR provides an advantage over rituximab maintenance is unknown. Currently, no data from randomized studies are available that would allow direct comparison of outcomes between these different consolidation approaches.
NCCN Recommendations
Based on evidence from the phase III randomized study in elderly patients with MCL, the NCCN NHL Panel recommended the inclusion of rituximab maintenance as postinduction consolidation for patients in remission after first-line R-CHOP who are not eligible to undergo consolidation with HDT/ASCR (see MANT-3, page 1494). The recommended dose schedule for rituximab maintenance (derived from the phase III study) is rituximab 375 mg/m2 every 8 weeks until disease progression (see MANT-A 1 of 3, page 1495).
Conclusions
These NCCN Guidelines Insights for NHL highlight several key updates and changes to the management of patients with CLL and the most common B-cell lymphomas, FL and DLBCL. Clinicians are encouraged to consult the full version of the 2012 Guidelines for NHL (to view the most recent version of these guidelines, visit NCCN.org). Although these updates are derived from evaluation of the most current available evidence at the time of the annual panel meetings (or at the time of an interim panel meeting held in response to publication or presentation of potentially practice-changing clinical data), the NCCN NHL Panel recognizes that guidelines updates are an iterative process given the rapidly evolving field of cancer research. Moreover, every patient with NHL presents with a unique set of patient- and disease-related factors that influence the course of treatment. Thus, to provide optimal and individualized disease management strategies for each patient, clinicians must use their clinical judgment when interpreting the recommendations put forth in the guidelines. The NCCN NHL Panel also emphasizes the importance of participation in prospective clinical trials when possible and appropriate for the patient.
References
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Robak T, Dmoszynska A, Solal-Celigny P et al.. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756–1765.
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Eichhorst B, Goede V, Hallek M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma 2009;50:171–178.
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Eichhorst BF, Busch R, Stilgenbauer S et al.. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382–3391.
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Foa R, Alietti A, Guarini A et al.. A phase II study of chlorambucil rituximab (CLB-R) followed by R maintenance vs observation in elderly patients with previously untreated chronic lymphocytic leukemia (CLL): induction phase results [abstract]. Haematologica 2011;96(Suppl 2):Abstract 532.
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Foa R, Ciolli S, Di Raimondo F et al.. Rituximab plus chlorambucil as initial treatment for elderly patients with chronic lymphocytic leukemia (CLL): effect of pre-treatment biological characteristics and gene expression patterns on response to treatment [abstract]. Blood 2011;118:Abstract 294.
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Hillmen P, Gribben JG, Follows GA et al.. Rituximab plus chlorambucil (R-Chlorambucil) as first-line treatment for chronic lymphocytic leukaemia (CLL): final analysis of an open-label phase II study [abstract] Ann Oncol 2011;22(Suppl 4):Abstract 120.
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Leoni LM, Bailey B, Reifert J et al.. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res 2008;14:309–317.
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Strumberg D, Harstrick A, Doll K et al.. Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs 1996;7:415–421.
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Knauf WU, Lissichkov T, Aldaoud A et al.. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009;27:4378–4384.
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Knauf WU, Lissitchkov T, Aldaoud A et al.. Bendamustine induces higher remission rates, prolongs progression free survival as well as time to next treatment, and improves overall survival for patients in complete remission without compromising quality of life when compared to chlorambucil in first line treatment of chronic lymphocytic leukemia [abstract]. Blood 2010;116:Abstract 2449.
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