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Recent developments in the treatment of aggressive non-Hodgkin lymphoma

Blood Reviews, 1, 23, pages 11 - 23

Summary

Options for treating aggressive non-Hodgkin lymphoma (NHL) have expanded in recent years. In phase 3 clinical trials, giving rituximab with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) every 3 weeks (R-CHOP-21) has been associated with improved survival, without increased toxicity, in all patient groups studied. Giving dose-dense CHOP – CHOP every 2 weeks (CHOP-14) – has also proved appropriate for all patients 18–75 years old. Studies combining these approaches – dose-dense CHOP with rituximab (R-CHOP-14) – have shown improved survival over CHOP-14 in patients 60–81 years old. These results also indicate the importance of delivering chemotherapy at full dose and on schedule, which can improve survival in aggressive NHL. Effective delivery of dose-dense regimens requires granulocyte colony-stimulating factor support, which should also be considered for standard CHOP. A key question for the future is whether R-CHOP-14 is superior to R-CHOP-21.

Keywords: Non-Hodgkin lymphoma, Diffuse large B-cell lymphoma, CHOP, CHOEP, Rrituximab, Dose intensity, Dose dense, Dose densification, Granulocyte colony-stimulating factor.

Introduction

Non-Hodgkin lymphoma (NHL) remains a substantial contributor to the incidence of and mortality associated with cancer in Europe. European cancer registry data suggest that the incidence of NHL increased until the mid-1990s, then began to plateau.1, 2, 3, and 4 In 2006, an estimated 72,800 new cases were diagnosed, 5 up from 62,300 in 2004. 6 NHL accounted for 3.2% of new cancer cases and 2.8% of cancer deaths in Europe in 2006, making it the eighth leading cause of new cancer cases and the 10th leading cause of cancer deaths. 5

The most common form of NHL is diffuse large B-cell lymphoma (DLBCL), which accounts for 31% of NHL cases. 7 The incidence of DLBCL increases with advancing age, such that the disease represents 54% of NHL cases among patients older than 75 years. 8 For nearly three decades, the standard of care for patients with DLBCL was cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP), which was established in 1976 as a regimen that induced high rates of overall response and complete remission in patients with advanced NHL. 9 CHOP later proved to be superior to third-generation regimens in terms of cost and severe toxicity, and similar to them in terms of disease-free and overall survival rates.10 and 11 Still, the cure rate with CHOP was suboptimal, with 3-year progression-free survival (PFS) and overall survival (OS) rates of about 40% and 50%, respectively. 10

Another problem was that physicians were circumspect in treating people over 60 years of age, who constitute 40% of patients with aggressive NHL. 12 Even after CHOP was established as the standard of care, many older patients with DLBCL were treated without doxorubicin, or treatment was completely withheld because of concerns about cardiotoxicity and other potential side effects. According to an analysis of a Dutch population-based NHL registry that studied CHOP in patients with DLBCL registered between 1981 and 1989 and stratified into five age groups (<60, 60–64, 65–69, 70–74, and >75 y), rates of complete response (CR) progressively declined after age 65, and relative 5-year OS progressively declined after age 60. 8

This paper reviews studies of three strategies that have been pursued to improve outcomes for patients with DLBCL: the addition of rituximab to CHOP (R-CHOP); dose intensification of CHOP, by either dose escalation or densification; and dose intensification of R-CHOP. It also discusses the link between maintaining dose intensity and improving survival in aggressive NHL.

Evolution of R-CHOP as the standard of care

Rituximab is a human-murine IgG1 monoclonal antibody against the B-cell surface antigen CD20, which is routinely expressed in patients with DLBCL. The first randomized trial of a rituximab-chemotherapy combination in lymphoma was the LNH98-5 trial of the Groupe d’Etude des Lymphomes de l’Adulte (GELA), which compared R-CHOP with CHOP in older patients (60–80 y) with DLBCL. 13 At a median follow-up of 2 years, the results showed that R-CHOP significantly increased either the CR rate and improved event-free survival (EFS) or OS and strongly decreased the rates of treatment failure and relapse, compared with standard CHOP alone. These improvements occurred in patients ⩾70 years old and in those with scores of 2 or 3 on the international prognostic index (IPI), as well as in lower-risk patients, and there was no clinically significant increase in toxicity. Table 1 gives details of this trial and the others discussed in this section.

Table 1 Comparisons of CHOP vs. R-CHOP

Study Population Design a Primary outcome measure(s) (95% CI) Safety results
GELA LNH98-5 13 399 patients with untreated DLBCL, age 60–80 y Random assignment to 8 cycles of CHOP or R-CHOP 2-y EFS: No significant difference between groups in clinically relevant toxicity
CHOP: 38% (32–45%)
R-CHOP: 57% (50–64%)
P < 0.001
         
Longer-term analysis of GELA LNH98-5 14 As above As above 5-y EFS: No long-term toxicity appeared to be associated with R-CHOP
CHOP: 29% (23–36%)
R-CHOP: 47% (40–54%)
P = 0.00002
         
US intergroup trial 15 632 patients with untreated DLBCL, age ⩾60 y Random assignment to CHOP or R-CHOP (6 or 8 cycles, depending on response after 4 cycles; R was administered 7 and 3 days before cycle 1, and 2 days before cycles 3, 5, and 7) 3-y FFS after induction therapy: Not reported
CHOP: 46%
R-CHOP: 53%
HR = 0.78 (0.61–0.99), P = 0.04
  Estimated 2-y FFS after second random assignment:
  Maintenance R: 76%
  Observation: 61%
  415 responders to CHOP or R-CHOP were randomly assigned to observation or maintenance R (4 courses at 6-mo intervals) HR = 0.63 (0.44–0.90), P = 0.009
         
Canadian population-based analysis 16 292 patients with advanced DLBCL, median age 64 y (range, 19–86 y) Retrospective database analysis comparing 140 patients treated with CHOP-like chemotherapy (median follow-up 42 mo) and 152 patients treated with CHOP-like chemotherapy + R (median follow-up 24 mo) 2-y PFS: Not reported
Without R: 51%
With R: 69%
RR = 0.56 (0.39–0.81), P = 0.002
2-y OS:
Without R: 52%
With R: 78%
RR = 0.40 (0.27–0.61), P < 0.0001
         
MInT 17 326 patients b age 18–60 y, with good-prognosis untreated DLBCL (aaIPI = 0–1 in stage II–IV disease, or stage I disease with bulk) Random assignment to 6 cycles of CHOP-like chemotherapy alone or with R Estimated 3-y EFS: No significant difference between groups in frequency of adverse events
Without R: 68% (62–73%)
With R: 85% (81–89%)
P < 0.0001

a Regimens were given at standard doses unless otherwise specified.

b Trial was stopped early; 824 patients were enrolled.

Abbreviations: aaIPI, age-adjusted international prognostic index; CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone; CI, confidence interval; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; FFS, failure-free survival; GELA, Groupe d’Etude des Lymphomes de l’Adulte; HR, hazard ratio; MInT, MabTher International Trial; mo, months; OS, overall survival; PFS, progression-free survival; R, rituximab; RR, risk ratio; y, year(s).

Longer-term analysis of GELA LNH98-5 showed that the survival benefits extended to 5 years ( Fig. 1 ), and no long-term toxicity was associated with R-CHOP. 14 The researchers attributed the longer survivals in the R-CHOP group to a lower rate of disease progression during therapy and fewer relapses among patients who had CR; this effect was still evident at 7 years. 18

gr1

Figure 1 Survival advantage with R-CHOP vs. CHOP in the GELA LNH98-5 trial at median follow-up of 5 years. 14 Figure reproduced with kind permission of the American Society of Clinical Oncology. 14

A US Intergroup study also compared R-CHOP and CHOP in older patients (⩾60 y). 15 By way of double randomization, the trial addressed the two major types of treatment failure in aggressive NHL: failure of induction therapy and failure to maintain CR. 12 Patients were initially assigned to R-CHOP or CHOP, and responders received either no additional treatment or maintenance rituximab for 2 years. Whether rituximab was part of induction therapy or maintenance after CHOP, it significantly improved failure-free survival (FFS, the time from random assignment to relapse, non-protocol treatment, or death), although its continuing use after R-CHOP was not beneficial.

After the 2-year results of GELA LNH98-5 were published, the British Columbia (Canada) Cancer Agency recommended R-CHOP for all newly diagnosed patients with advanced DLBCL, regardless of age. Investigators then retrospectively analyzed the outcomes of such patients during a 3-year period, 18 months before and after the policy was implemented. 16 By making the patient selection process dependent on diagnosis, not treatment, in that it included all patients newly diagnosed with biopsy-proven, advanced DLBCL within the study interval, Sehn et al. concluded that the availability of a new treatment should not have biased patient inclusion. The analysis showed that regardless of patient age, both PFS and OS were significantly better in patients who received rituximab than in those treated solely with CHOP-like chemotherapy, even after the investigators controlled for age and IPI score. Even considering the different lengths of follow-up for the two groups, this study is very important because it reflects “real life” and the study design minimized selection bias.

The benefits of R-CHOP also extend to younger adults with DLBCL who have a good prognosis. The MabThera international trial (MInT), designed by cooperative groups from 18 countries, was stopped early when it demonstrated the superiority of R-CHOP over CHOP in that patient population. 17 At median follow-up of 34 months, EFS, PFS, and OS were significantly better in patients who received rituximab plus CHOP or CHOP-like chemotherapy than in those who received only chemotherapy. Only 21% of patients failed after chemotherapy plus rituximab, compared with 41% who failed after chemotherapy alone, suggesting that the proportion of young patients who need salvage treatment could be halved with rituximab. CHOEP (CHOP plus etoposide) was superior to CHOP with regard to EFS, but the comparison of R-CHOP and R-CHOEP showed no significant difference in EFS or overall survival. R-CHOP is therefore preferable to R-CHOEP because it has fewer toxic effects and is a 1-day regimen.

Thus, the addition of rituximab to CHOP has been associated with improvements in OS and in EFS or PFS, without increased toxicity, in all patient groups studied (no data have been published on younger patients at high-risk). The addition of rituximab to CHOP is now considered the standard of care for treatment of DLBCL with curative intent. 19

Dose intensification of CHOP and CHOP-like regimens

Concurrent with the studies of rituximab, investigators have been examining whether they might improve outcomes in patients with aggressive lymphoma by increasing the chemotherapy dose intensity (the amount of drug delivered per unit of time). Dose intensification can be accomplished through dose escalation (increasing the amount of drug given per cycle) or dose densification (reducing the time between treatment cycles).

A study that investigated both approaches has been conducted by the German High-grade NHL Study Group (DSHNHL). In its NHL-B trial, conventional CHOP delivered every 3 weeks (CHOP-21) was intensified in three ways: by adding etoposide (CHOEP-21), reducing the interval between cycles to 2 weeks (CHOP-14), or both (CHOEP-14). The every-2-week regimens were supported with mandatory prophylactic granulocyte colony-stimulating factor (G-CSF), whereas in the every-3-week regimens, G-CSF was administered at the treating physician’s discretion. The primary endpoint was EFS. The NHL-B trial enrolled two distinct patient populations.

NHL-B1 involved subjects 18–60 years old who had a good prognosis.20 and 21 In pair-wise comparisons, estimated 5-year EFS was similar for the every-3-week and every-2-week regimens, but it was significantly better with the CHOEP regimens than with the CHOP regimens. All regimens were well tolerated, and the researchers concluded that CHOEP should be preferred for younger patients with good-prognosis aggressive NHL. An exploratory direct comparison showed no significant advantage of CHOEP-14 over CHOEP-21.

Conversely, in the NHL-B2 trial involving older patients, 61–75 years old, CHOEP-21 and especially CHOEP-14 were found to be substantially more toxic than the CHOP regimens.21 and 22 Of the three non-standard regimens studied in the older patients, CHOP-14 was associated with the lowest overall rate of World Health Organization grade 3 or 4 adverse events and the fewest therapeutic interventions. When the efficacy of CHOP-21 was compared to the other three regimens, only CHOP-14 significantly improved 5-year EFS or OS.

Other data from the NHL-B trial suggest that the toxicity of CHOP-14 + G-CSF is comparable to that of CHOP-21 without G-CSF. 21 Therefore, CHOP-14 + G-CSF should also be considered an appropriate treatment for all patients between the ages of 18 and 75, who have aggressive NHL. Table 2 gives details of the NHL-B trial and the others discussed in this section.

Table 2 Studies of dose intensification of CHOP and CHOP-like chemotherapy

Study Population Design a Primary outcome measure(s) (95% CI) Safety results
DSHNHL NHL-B120 and 21 710 patients, age 18–60 y, with untreated good-prognosis aggressive NHL (normal LDH) Random assignment to 6 cycles of CHOP-21, CHOEP-21 (CHOP-21 + E 100 mg/m2 days 1–3), CHOP-14 + G-CSF, or CHOEP-14 + G-CSF Estimated 5-y EFS: All regimens were well tolerated
CHOEP regimens: 69% (64–74%)
CHOP regimens: 58% (52–63%)
P = 0.004
CHO(E)P-21: 62% (57–67%)
CHO(E)P-14: 65% (60–71%)
P = 0.622
DSHNHL NHL-B220 and 21 689 patients, age 61–75 y, with untreated aggressive NHL As above 5-y EFS compared with CHOP-21 b : CHOEP-21 and especially CHOEP-14 were significant more toxic than the CHOP regimens, which had similar toxicity
CHOP-14: RR = 0.66 (0.50–0.87), P = 0.003
CHOEP-21: RR = 0.82 (0.63–1.07), P = 0.145
CHOEP-14: RR = 0.77 (0.59–1.02), P = 0.064
DSHNHL 23 389 patients, age 18–60 y, with good-prognosis aggressive NHL (aaIPI = 0 or 1). Random assignment to CHOEP-21 as given in NHL-B1 or to Hi-CHOEP (C: 1400 mg/m2; H: 65 mg/m2, O: 2 mg; E: 175 mg/m2 × 3; P: 100 mg × 5) TTF at median follow-up of 37 mo: Hematologic toxicity and risk of infection were significantly greater with Hi-CHOEP than with CHOEP-21
CHOEP-21: 64%
Hi-CHOEP: 68%
P = 0.639
HOVON-26 27 477 patients, age 16–65 y, with untreated intermediate-risk aggressive NHL Random assignment to 8 cycles of CHOP-21 or 6 cycles of I-CHOP-14 + G-CSF (C: 1000 mg/m2, H: 70 mg/m2, O: 2 mg; P: 100 mg × 5) CRu at median follow-up of 50 mo: Clinically relevant side effects occurred more often with I-CHOP
CHOP-21: 49%
I-CHOP-14: 53%
P = 0.41
Estimated 6-y OS:
CHOP-21: 50%
I-CHOP-14: 61%
HR = 0.83 (0.62–1.11), P = 0.20

a Regimens were given at standard doses unless otherwise specified.

b Multivariate model adjusted for the stratification variables lactate dehydrogenase, stage, and bulky disease. The planned 2 × 2 factorial analysis was not possible because in a proportional hazard model for EFS, a significant interaction was found between the two treatment factors (interval reduction and addition of etoposide) (RR = 1.50, P = 0.041).

Abbreviations: -14, repeated every weeks; -21, repeated every 3 weeks; aaIPI, age-adjusted international prognostic index; C, cyclophosphamide; CHOEP, CHOP plus etoposide; CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone; CI, confidence interval; CRu, complete response (unconfirmed); DSHNHL, German High-Grade NHL Study Group; E, etoposide; EFS, event-free survival; G-CSF, granulocyte colony-stimulating factor; H, hydroxyldaunorubicin (doxorubicin); HOVON, Dutch Haemato-Oncology Association; HR, hazard ratio; LDH, lactate dehydrogenase; mo, months; NHL, non-Hodgkin lymphoma; O, vincristine; OS, overall survival; P, prednisone; RR, risk ratio; TTF, time to treatment failure; y, year(s).

Findings from two recently published trials provide evidence that, in contrast to dose densification and/or the addition of rituximab, dose escalation is not as promising for younger patients with NHL. Wishing to improve further on the results of the NHL-B1 trial, the DSHNHL conducted a randomized study to compare standard CHOEP-21 with a dose-escalated version in younger patients with aggressive NHL and a good prognosis. 23 The dose-escalated regimen comprised cyclophosphamide 1400 mg/m2, doxorubicin 65 mg/m2, vincristine 2 mg, etoposide 175 mg/m2 for 3 cycles (×3), and prednisone 100 mg × 5. Dose-escalated CHOEP-21 was considerably more toxic than standard treatment, and there was no difference in time to treatment failure (TTF, the primary endpoint) or OS. Neither the low-risk nor the low-intermediate-risk subgroup benefited from dose escalation.

For younger patients with intermediate-risk aggressive NHL, the Dutch Haemato-Oncology Association (HOVON) took a hybrid approach to dose intensification. In a randomized study launched in 1994, standard CHOP was compared with intensified 12-week CHOP (I-CHOP) comprising cyclophosphamide 1000 mg/m2, doxorubicin 70 mg/m2, vincristine 2 mg, and prednisone 100 mg × 5. 24 Patients were treated every 2 weeks for 6 cycles, so the same amounts of cyclophosphamide and doxorubicin were delivered in 12 weeks as would be delivered in 24 weeks of standard CHOP. The aim was to double the dose intensity without increasing the cumulative dose. G-CSF was given in the I-CHOP arm only. The two primary endpoints, CR and OS, were not significantly different between groups. When patients were subdivided by IPI score, I-CHOP was associated with improvement in OS and DFS, compared with CHOP-21, but only in the low-intermediate-risk group, and the differences were of borderline significance. Noting that R-CHOP has become the standard of care for aggressive B-cell lymphoma, the researchers recommend combining I-CHOP with rituximab for younger patients with low-risk and low-intermediate-risk aggressive NHL. 24 However, because the subgroup analysis was unplanned, the results were not definitive, and rituximab was not part of the protocol, this approach needs further study prior to ratification as a recommendation.

Dose intensification of R-CHOP

Patients with DLBCL whose IPI scores indicate they are at high-intermediate or high-risk have less than a 50% chance of being cured with R-CHOP-21. 25 Even in the MInT study of younger adults with a good prognosis, outcomes varied among those who received rituximab plus CHOP-like chemotherapy: in the less favorable group (bulky disease, age-adjusted IPI [aaIPI] ⩾1, or both), 3-year EFS with rituximab was 78%, compared with 97% in the more favorable group (aaIPI = 0, no bulky disease). 17 Now that addition of rituximab to CHOP has become the standard of care for DLBCL, investigators are examining the effects of administering both rituximab and CHOP every 2 weeks (see below).

The DSHNHL’s RICOVER-60 trial, the largest randomized trial in DLBCL performed to date, compared 6 versus 8 cycles of CHOP-14 with or without rituximab (all arms with G-CSF support) in more than 1200 older patients (60–81 y) with CD20+ DLBCL. 26 Using 6 cycles of CHOP-14 (6 × CHOP-14) as the comparator, EFS was significantly better in both rituximab arms ( Table 3 ), but OS was significantly better only with 6 × R-CHOP-14. In fact, results with 6 × R-CHOP-14 + G-CSF are the best ever reported for older patients with CD20+ DLBCL, and this regimen will be the reference standard in future DSHNHL trials of DLBCL treatment for older patients. However, outside Germany, most physicians consider that the benefit of R-CHOP-14 is not proven and that it is more toxic than standard R-CHOP-21. Two randomized studies are currently looking at R-CHOP every 2 weeks, but until their results become available R-CHOP-21 will remain the standard of care in most countries.

Table 3 Studies of dose intensification of R-CHOP

Study Population Design a Primary outcome measure(s) (95% CI) Safety results
DSHNHL RICOVER-60 26 1222 patients, age 61–80 y, with DLBCL Random assignment to 6 or 8 cycles of CHOP-14, with or without R (regardless of the number of cycles, 8 R infusions were given) Estimated 3-y EFS: Not reported
6 × CHOP-14: 47%
8 × CHOP-14: 53%
6 × R-CHOP-14: 66%
8 × R-CHOP-14: 63%
EFS compared with 6 × CHOP-14 b :
8 × CHOP-14: RR = 0.76, P = 0.017
6 × R-CHOP-14: RR = 0.51,P < 0.001
8 × R-CHOP-14: RR = 0.54,P < 0.001
         
HOVON 30 243 patients, a age ⩾65 y, with untreated intermediate- or high-risk B-cell NHL 8 cycles of CHOP-14 with random assignment to receive or not receive 6 infusions of R (G-CSF support in both arms) Estimated 2-y FFS: 64% of patients completed planned treatment; 22% of patients went off treatment due to toxicity; 15% of patients < 70 y went off treatment due to toxicity
CHOP-14: 33%
R-CHOP-14: 55%
HR = 0.60, P = 0.007

a Trial was stopped early; 261 patients were enrolled.

b Multivariate model adjusted for the stratification variables lactate dehydrogenase, stage, performance status, bulky disease, number of extranodal sites, and age.

Abbreviations: -14, repeated every weeks; -21, repeated every 3 weeks; CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone; CI, confidence interval; DLBCL, diffuse large B-cell lymphoma; DSHNHL, German High-grade NHL Study Group; FFS, failure-free survival; G-CSF, granulocyte colony-stimulating factor; HOVON, Dutch Haemato-Oncology Association; HR, hazard ratio; mo, months; NHL, non-Hodgkin lymphoma; R, rituximab; RR, risk ratio; y, year(s).

A subgroup analysis of the RICOVER-60 data showed no difference in efficacy between 6 and 8 cycles of therapy in patients with either good or poor prognosis. 27 In contrast, in both subgroups, TTF was significantly better with R-CHOP-14 than with CHOP-14.

Before and after rituximab infusion during each cycle in RICOVER-60, blood samples were taken from 18 participants in the R-CHOP-14 arm. According to pharmacokinetic analysis, rituximab levels reached their nadir after the first cycle of R-CHOP-14, then increased after each subsequent cycle. The researchers speculate that the nadir would be even lower in an every-3-week schedule of R-CHOP. Thus, as the researchers note, it appears that dose-dense rituximab (given every 2 weeks), not just dose-dense CHOP, contributed to the excellent results of the RICOVER-60 trial. The DSHNHL investigated dose-dense rituximab in combination with CHOP-14 in an ongoing phase 1 and 2 study, and the early results are encouraging. 28

Another finding from the pharmacokinetic analysis of RICOVER-60 was that pre-infusion rituximab serum levels increased with each additional administration for the first 4 cycles, then leveled off. 29 This finding has prompted the DSHNHL to study whether dose escalation of rituximab in the early cycles of R-CHOP-14 might further improve outcomes.

Somewhat similar to RICOVER-60, a study conducted by HOVON and the Nordic Lymphoma Group compared CHOP-14 and R-CHOP-14 (both arms with G-CSF support) in older patients, age >65 years. 30 This trial was stopped early because the addition of rituximab to CHOP-14 significantly improved the primary outcomes. As shown in Table 3 , the results were not as impressive as those of RICOVER-60, but are encouraging owing to the fact that >60% of these older patients, with a median age of 72 years, tolerated the regimen.

Now that R-CHOP-21 is standard in most countries and CHOP-14 has been shown to be effective in many patients, a key research question is whether R-CHOP-14 produces further benefit than R-CHOP-21. Two ongoing trials are addressing this issue by comparing R-CHOP-21 with R-CHOP-14 head to head. In GELA LNH03-6B, patients between 66 and 80 years old who had DLBCL and an aaIPI score ⩾1 were randomly assigned to 8 cycles of R-CHOP-21 or R-CHOP-14. 31 A multicenter randomized trial headquartered at University College London is making the same comparison in a broader patient population, individuals 18 years or older with untreated DLBCL. 32

Maintaining planned dose intensity

CHOP-based therapy has a number of dose-limiting toxicities, such as chemotherapy-induced neutropenia, particularly in older patients. In the NHL-B2 trial, the most common grade 3 or 4 toxicity was leukocytopenia, which occurred in 72% of patients who received CHOP-21 and in 70% of those treated with CHOP-14. 20 Grade 3 or 4 thrombocytopenia occurred in 8% and 15% of patients, respectively, and grade 3 or 4 anemia affected 13% and 20%, respectively. Along with alopecia and nausea or vomiting, common non-hematologic grade 3 or 4 toxicities were infection, cardiac toxicity, neurologic toxicity, lung toxicity, and, in the CHOP-14 arm, mucositis.

If CHOP side effects require dose reductions, dose delays, or chemotherapy withdrawal, patient survival can be negatively affected by the reduction in relative dose intensity (RDI, the proportion of the intended chemotherapy dose that a patient receives during a specified time period). In Belgium and the United Kingdom, audits of 289 NHL patients receiving CHOP-21 showed that 5-year OS was significantly associated with RDI ⩽90% (hazard ratio,1.8; 95% confidence interval [CI], 1.1–2.8). 33 These observations confirm earlier reports of associations between reduced RDI and reduced OS in patients with NHL.34, 35, 36, and 37

Research conducted in routine community practice has documented that febrile neutropenia (FN) is a common cause of reduced RDI in patients with NHL. At 16 Spanish hospitals, researchers examined the charts of 67 adults with lymphoma who had one or more FN episodes related to cytotoxic chemotherapy. 38 FN occurred in the first chemotherapy cycle in 61% of these patients. Dose reductions were required for 17% of patients, dose delays for 24%, and treatment withdrawal for 15%. In Western Europe, a prospective observational study by Pettengell et al. examined the impact of FN on chemotherapy in 34 centers. 39 Of 240 patients with NHL, most received CHOP-like-21 (74%) or CHOP-like-14 (17%) chemotherapy. FN occurrence was ⩾20% with CHOP-like-21 and most other NHL regimens. For patients with NHL, the mean RDI was only 86%, and 32% of patients had low RDI (⩽85%). Other risk factors for low RDI were advancing age, Eastern Cooperative Oncology Group performance status ⩾2, fewer cycles of CSF administration, and first-cycle FN.

Pettengell et al. (2006) 39 conclude that routine European practice should be revised to include primary prophylaxis with G-CSF if the patient will receive a chemotherapy regimen associated with an FN incidence ⩾20% or is expected to receive less than optimal RDI. This recommendation is in line with recently published guidelines of the European Organisation for Research and Treatment of Cancer (EORTC), 40 which conclude that there is strong and consistent evidence that G-CSF prophylaxis can maintain chemotherapy at the desired dose intensity or density and minimize delays. The EORTC guidelines recommend routine G-CSF prophylaxis in any circumstances in which reductions in dose intensity or density are known to be associated with poor prognosis. Specific examples include patients who are receiving:

  • A regimen associated with ⩾20% overall risk of FN.
  • A regimen associated with FN risk of 10–20%, when patient-related factors increase that risk above 20% (e.g., age, previous FN, advanced disease ( Fig. 2 shows all the factors to be considered)).
  • Dose-dense or dose-intense chemotherapy that has survival benefits.
  • Adjuvant therapy, potentially curative treatment, or treatment intended to prolong survival.
gr2

Figure 2 EORTC guidelines for use of G-CSF with cytotoxic chemotherapy. 40 Figure reproduced with kind permission of Elsevier. 40

The guidelines state that CHOP-21 is associated with an FN risk of >20% and R-CHOP-21 carries a 10–20% risk of FN. In addition, R-CHOP-14, a dose-dense regimen, also needs G-CSF support. CHOP-14 is not mentioned but, because it is a dose-dense regimen that has survival benefits, it falls in the general category discussed above that calls for routine G-CSF prophylaxis. Several recent studies have demonstrated the efficacy of once-per-cycle pegfilgrastim in supporting CHOP-14 41 and R-CHOP-14.42, 43, and 44

Like EORTC, the American Society of Clinical Oncology (ASCO) 45 and the National Comprehensive Cancer Network 46 advise primary G-CSF prophylaxis when the risk of chemotherapy-induced FN is ⩾20%.

Non-Hodgkin’s lymphoma is primarily a disease of the elderly, with more than 60% of all cancers occurring in those aged 65 years or older. 47 Maintaining planned dose intensity is a particularly important concern in the treatment of older patients. Compared with younger individuals with NHL, older patients are more likely to require dose delays and dose reductions.48 and 49 In fact, older age is the patient-related factor most consistently associated with an increase in FN risk. 40

Since 2003, EORTC has recommended that prophylactic G-CSF should be used to support the administration of planned doses on schedule in all older patients receiving myelotoxic chemotherapy. 50 The 2006 EORTC guidelines affirm that in evaluating the overall FN risk prior to each cycle of chemotherapy, particular consideration should be given to the elevated risk of FN in patients ⩾65 years. 40

In older adults with DLBCL who are treated with CHOP or R-CHOP, FN is most common during the first cycle of chemotherapy, 51 and first neutropenia-related hospitalizations in older adults with NHL are most common during the first 2 cycles. 52 These observations suggest that G-CSF should be used starting in the first cycle in older patients. In a randomized study of NHL patients ⩾65 years who were being treated in community practice, first-cycle pegfilgrastim significantly lowered the risk of FN associated with R-CHOP and other regimens, compared with pegfilgrastim used after cycle 1 at the physician’s discretion (15% [95% CI, 8–25%] vs. 37% [95% CI, 26–49%], P = 0.0043). 53

The future of therapy for aggressive NHL

The success of rituximab in the treatment of aggressive NHL has prompted the investigation of monoclonal antibodies that target other surface proteins and antigens commonly expressed in B-cell lymphoma.

The most promising are antibodies against CD40, the B-cell-activating factor of the TNF family (BAFF), and receptors for TRAIL (TNF-α-related apoptosis-inducing ligand, also known as Apo2L). 54 Another approach is to use small molecules to target intracellular pathways that have a role in tumor cell survival and growth. For example, a multicenter phase 2 study using bortezomib, a proteasome inhibitor, in patients with relapsed or refractory mantle cell lymphoma, showed that it provided substantial activity in terms of durable and complete response, with predictable and manageable toxicity. 55 Although the effort is largely theoretical at this time, it may also be possible to identify small molecules to target certain classes of mitotic kinases that regulate cell division and mitosis. Finally, researchers are combining bevacizumab or thalidomide with rituximab, CHOP, or R-CHOP to determine whether it might be worthwhile to target tumor angiogenesis in NHL.

Most of these agents and regimens are still in early development, but it seems likely that at least a few more targeted therapies for NHL will soon be available.

Conclusions

The addition of rituximab to CHOP, dose intensification of CHOP, and dose densification of R-CHOP are important advances in the treatment of NHL. The results of ongoing studies will refine treatment further. The key unanswered question at the moment is whether R-CHOP-14 results in better outcomes than R-CHOP-21. Another prominent subject of ongoing research is the role of dose densification of rituximab. The ability to deliver full dose on schedule has an important effect on survival in patients with NHL, and it is of note that CHOP-21, R-CHOP-21, CHOP-14, and R-CHOP-14 are all associated with a high-risk of grade 3 or 4 neutropenia and FN, which often result in reduced RDI. As suggested by the EORTC, ASCO, and NCCN guidelines, G-CSF prophylaxis is likely to be beneficial for patients receiving CHOP-14 or R-CHOP-14, and it should be considered, following careful review of patient-related risk factors for FN such as advanced age, for patients receiving CHOP-21 or R-CHOP-21.

Practice points

 

  • R-CHOP is considered the standard of care for treatment of DLBCL with curative intent.
  • CHOP-14 should also be considered an appropriate treatment for all patients between the ages of 18 and 75 who have aggressive NHL.
  • Research in European community practices has documented that FN is a common cause of dose reductions and delay in patients with NHL receiving CHOP-like regimens.
  • Effective delivery of dose-dense regimens requires granulocyte colony-stimulating factor support, which should also be considered for standard CHOP.
  • The EORTC recommends primary G-CSF prophylaxis when the overall risk of chemotherapy-induced FN is ⩾20% and to support the administration of planned doses on schedule in older patients receiving myelotoxic chemotherapy.

Research agenda

 

  • Is R-CHOP-14 superior to R-CHOP-21?

Conflict of interest statement

Dr. Coiffier has participated in speaker’s bureaus for Amgen, Roche, and Genentech. He has also served on advisory boards for Amgen and Roche. Dr. Michallet has no potential conflicts of interest.

Acknowledgements

The authors thank Faith Reidenbach and Supriya Srinivasan, Ph.D. for writing and editorial support. Amgen (Europe) GmbH sponsored an external agency for writing support.

References

  • 1 S. Sandin, H. Hjalgrim, B. Glimelius, K. Rostgaard, E. Pukkala, J. Askling. Incidence of non-Hodgkin’s lymphoma in Sweden, Denmark, and Finland from 1960 through 2003: an epidemic that was. Cancer Epidemiol Biomarkers Prev. 2006;15:1295-1300
  • 2 G. Broccia, P. Cocco, P. Casula. Incidence of non-Hodgkin’s lymphoma and Hodgkin’s disease in Sardinia, Italy: 1974–1993. Haematologica. 2001;86:58-63
  • 3 M. Pollan, G. Lopez-Abente, C. Moreno, et al. Rising incidence of non-Hodgkin’s lymphoma in Spain: analysis of period of diagnosis and cohort effects. Cancer Epidemiol Biomarkers Prev. 1998;7:621-625
  • 4 G. Morgan, M. Vornanen, J. Puitinen, et al., for the Biomed Study Group. Changing trends in the incidence of non-Hodgkin’s lymphoma in Europe. Ann Oncol. 1997;8(Suppl. 2):49-54
  • 5 J. Ferlay, P. Autier, M. Boniol, M. Heanue, M. Colombet, P. Boyle. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007;18:581-592
  • 6 P. Boyle, J. Ferlay. Cancer incidence and mortality in Europe, 2004. Ann Oncol. 2005;16:481-488
  • 7 Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89:3909-3918
  • 8 E. Maartense, H.C. Kluin-Nelemans, S. le Cessie, P.M. Kluin, S. Snijder, E.M. Noordijk. Different age limits for elderly patients with indolent and aggressive non-Hodgkin lymphoma and the role of relative survival with increasing age. Cancer. 2000;89:2667-2676
  • 9 E.M. McKelvey, J.A. Gottlieb, H.E. Wilson, et al. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer. 1976;38:1484-1493
  • 10 R.I. Fisher, E.R. Gaynor, S. Dahlberg, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. New Engl J Med. 1993;328:1002-1006
  • 11 R.I. Fisher, E.R. Gaynor, S. Dahlberg, et al. A phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate- or high-grade non-Hodgkin’s lymphoma: results of SWOG-8516 (Intergroup 0067), the National High-priority Lymphoma Study. Ann Oncol. 1994;5(Suppl. 2):91-95
  • 12 International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. New Engl J Med. 1993;329:987-994
  • 13 B. Coiffier, E. Lepage, J. Briere, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. New Engl J Med. 2002;346:235-242
  • 14 P. Feugier, A. Van Hoof, C. Sebban, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117-4126
  • 15 T.M. Habermann, E.A. Weller, V.A. Morrison, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:3121-3127
  • 16 L.H. Sehn, J. Donaldson, M. Chhanabhai, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23:5027-5033
  • 17 M. Pfreundschuh, L. Trumper, A. Osterborg, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379-391
  • 18 B. Coiffier, P. Feugier, N. Mounier, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(18S) [Abstract 8009]
  • 19 L.M. Jost, O. Kloke, R.A. Stahel. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of newly diagnosed large cell non-Hodgkin’s lymphoma. Ann Oncol. 2005;16(Suppl. 1):i58-i59
  • 20 M. Pfreundschuh, L. Trumper, M. Kloess, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004;104:626-633
  • 21 A. Wunderlich, M. Kloess, M. Reiser, et al. Practicability and acute haematological toxicity of 2- and 3-weekly CHOP and CHOEP chemotherapy for aggressive non-Hodgkin’s lymphoma: results from the NHL-B trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol. 2003;14:881-893
  • 22 M. Pfreundschuh, L. Trumper, M. Kloess, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004;104:634-641
  • 23 M. Pfreundschuh, S. Zeynalova, U. Duehrsen, et al. Dose-escalated CHOP plus etoposide (Hi-CHOEP) is not superior to base-line CHOEP in young good-prognosis patients with aggressive lymphoma: results of a randomized DSHNHL trial. J Clin Oncol. 2006;24(18S) [Abstract 7513]
  • 24 L.F. Verdonck, A. Notenboom, D.D. de Jong, et al. Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood. 2007;109:2759-2766
  • 25 National Comprehensive Cancer Network. Non-Hodgkin’s lymphomas: the national comprehensive cancer network clinical practice guidelines in oncology, version 1.2007; March 2, 2007. <http://www.nccn.org> [accessed 14.05.07].
  • 26 M. Pfreundschuh, J. Schubert, M. Ziepert, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9:105-116
  • 27 J. Schubert, M. Reiser, M. Wenger, et al. Bi-weekly dosing preserves the efficacy of rituximab in elderly patients with poor-prognosis DLBCL: results from the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study group (DSHNHL). J Clin Oncol. 2006;:24 [Abstract 7536]
  • 28 V. Poeschel, M. Nickelsen, M. Hanel, et al. Dose-dense rituximab in combination with biweekly CHOP-14 for elderly patients with diffuse large B-cell lymphoma(DLBCL): results of a phase-I/II and pharmacokinetic study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood. 2006;108:774a
  • 29 M. Reiser, M. Wenger, C. Nickenig, N. Peter, B. Metzner, M. Pfreundschuh. Serum levels and pharmacokinetic of rituximab in bi-weekly R-CHOP in elderly patients with DLBCL treated in the RICOVER-60 trial. J Clin Oncol. 2006;24(18S) [Abstract 7537]
  • 30 P. Sonneveld, W. van Putten, B. Biesma, et al. Phase III trial of 2-weekly CHOP with rituximab for aggressive B-cell non-Hodgkin’s lymphoma in elderly patients. Blood. 2006;:108 [Abstract 210]
  • 31 R. Delarue, N. Mournier, C. Haioun, et al. Safety of prophylactic use of darbepoetin alfa in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP 14 or R-CHOP21: preliminary results of the LNH03-6B randomized GELA study. Blood. 2006;:108 [Abstract 2436]
  • 32 UK Clinical Research Network. A phase III multicentre randomised clinical trial comparing rituximab with CHOP given every 14 days and rituximab with CHOP given every 21 days for the treatment of patients with newly diagnosed diffuse large B cell non-Hodgkin’s lymphoma. UKCRN ID 1437. <http://pfsearch.ukcrn.org.uk/StudyDetail.aspx?TopicID=1&StudyID=1437> [accessed 18.06.07].
  • 33 A. Bosly, D. Bron, A. Van Hoof, et al., for the Lymphoma Dose Project: a National Study. Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. Ann Hematol. 2008;87:277-283
  • 34 K.W. Lee, D.Y. Kim, T. Yun, et al. Doxorubicin-based chemotherapy for diffuse large B-cell lymphoma in elderly patients: comparison of treatment outcomes between young and elderly patients and the significance of doxorubicin dosage. Cancer. 2003;98:2651-2656
  • 35 E. Lepage, C. Gisselbrecht, C. Haioun, et al., for the Groupe d’Etude des Lymphomes de l’Adulte. Prognostic significance of received relative dose intensity in non-Hodgkin’s lymphoma patients: application to LNH-87 protocol. Ann Oncol. 1993;4:651-656
  • 36 R. Epelbaum, D. Faraggi, Y. Ben-Arie, et al. Survival of diffuse large cell lymphoma: a multivariate analysis including dose intensity variables. Cancer. 1990;66:1124-1129
  • 37 L.W. Kwak, J. Halpern, R.A. Olshen, S.J. Horning. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol. 1990;8:963-977
  • 38 A. López, J.D. Alonso, J. Gómez-Codina, et al. Febrile neutropenia in lymphoma patients is associated with substantial resource use and healthcare costs in clinical practice in Spain. Blood. 2006;:108 [Abstract 5512]
  • 39 Pettengell R, Schwenkglenks M, Leonard R et al. Neutropenia occurrence and predictors of reduced chemotherapy delivery: results from the INC-EU prospective observational European neutropenia study. Support Care Cancer 2008 [Epub ahead of print].
  • 40 M.S. Aapro, D.A. Cameron, R. Pettengell, et al. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer. 2006;42:2433-2453
  • 41 M. Wolf, M. Bentley, P. Marlton, et al. Pegfilgrastim to support CHOP-14 in elderly patients with non-Hodgkin’s lymphoma. Leuk Lymphoma. 2006;47:2344-2350
  • 42 U.J. Mey, A. Maier, I.G. Schmidt-Wolf, et al. Pegfilgrastim as hematopoietic support for dose-dense chemoimmunotherapy with R-CHOP-14 as first-line therapy in elderly patients with diffuse large B cell lymphoma. Support Care Cancer. 2007;15:877-884
  • 43 E. Brusamolino, C. Rusconi, L. Montalbetti, et al. Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity. Haematologica. 2006;91:496-502
  • 44 Moore TD, Patel T, Segal ML et al. A single pegfilgrastim dose per cycle supports dose-dense (q14d) CHOP-R in patients with non-Hodgkin’s lymphoma. In: Presented at the 2003 annual meeting of the American Society of Hematology, December 7, 2003, San Diego, CA [Poster 2365].
  • 45 T.J.C. Smith, J. Khatcheressian, G.H. Lyman, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24:3187-3205
  • 46 National Comprehensive Cancer Network. Myeloid growth factors: the national comprehensive cancer network clinical practice guidelines in oncology, version 1.2007; December 8, 2006. <http://www.nccn.org> [accessed 14.05.07.
  • 47 L.A.G. Ries, M.P. Eisner, C.L. Kosary, et al. SEER cancer statistics review, 1973–1997. (National Cancer Institute, Bethesda (MD), 2000)
  • 48 G.H. Lyman, D.C. Dale, J. Friedberg, J. Crawford, R.I. Fisher. Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin Oncol. 2004;22:4302-4311
  • 49 V.A. Morrison, V. Picozzi, S. Scott, et al. The impact of age on delivered dose intensity and hospitalizations for febrile neutropenia in patients with intermediate-grade non-Hodgkin’s lymphoma receiving initial CHOP chemotherapy: a risk factor analysis. Clin Lymphoma. 2001;2:47-56
  • 50 L. Repetto, L. Biganzoli, C.H. Koehne, et al. EORTC cancer in the elderly task force guidelines for the use of colony-stimulating factors in elderly patients with cancer. Eur J Cancer. 2003;39:2264-2272
  • 51 V.A. Morrison, E.A. Weller, T.M. Habermann, et al. Patterns of growth factor usage and febrile neutropenia among older patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP: an intergroup experience (CALGB 9793, ECOG-SWOG 4494). Blood. 2004;:104 [Abstract 3309]
  • 52 S. Chen-Hardee, E.A. Chrischilles, M.D. Voelker, et al. Population-based assessment of hospitalizations for neutropenia from chemotherapy in older adults with non-Hodgkin’s lymphoma (United States). Cancer Cause Contr. 2006;17:647-654
  • 53 L. Balducci, H. Al-Halawani, V. Charu, et al. Elderly cancer patients receiving chemotherapy benefit from first-cycle pegfilgrastim. Oncologist. 2007;12:1416-1424
  • 54 L. Fayad, A. Younes. Novel treatment strategies for aggressive non-Hodgkin’s lymphoma. Expert Opin Pharmacother. 2006;7:733-748
  • 55 R.I. Fisher, S.H. Bernstein, B.S. Kahl, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24:4867-4874

Footnotes

Hématologie, CH Lyon-Sud, 69495 Pierre-Bénite, France

lowast Corresponding author. Tel.: +33 478 864300; fax: +33 478 864355.