Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

A Decade of Rituximab: Improving Survival Outcomes in Non-Hodgkins Lymphoma

Arturo Molina
Cougar Biotechnology, Los Angeles, California 90024; email: amolina@cougarbiotechnology.com

Annu. Rev. Med. 2008. 59:23750 First published online as a Review in Advance on July 16, 2007 The Annual Review of Medicine is online at http://med.annualreviews.org This articles doi: 10.1146/annurev.med.59.060906.220345 Copyright c 2008 by Annual Reviews. All rights reserved 0066-4219/08/0218-0237$20.00

Key Words
monoclonal antibody, immunotherapy, CD20 antigen, follicular lymphoma, diffuse large B cell lymphoma

Abstract
The anti-CD20 monoclonal antibody rituximab, rst approved for clinical use in 1997, has changed the standard of care for many patients with non-Hodgkins lymphoma (NHL). Recent data from large randomized clinical trials conrm that the addition of rituximab to standard chemotherapy regimens (chemoimmunotherapy) improves both response rates and survival outcomes in patients with follicular NHL and diffuse large B cell lymphoma (DLBCL), the two most common subtypes of NHL. Population-based analyses have found substantial improvements in NHL survival over the past decade; studies indicate that rituximab has favorably altered the longterm prognosis of follicular NHL and DLBCL patients. This review discusses the clinical development of rituximab-based therapies for patients with low-grade or follicular NHL and newly diagnosed DLBCL, highlighting recent key randomized trials with a focus on survival outcomes.

237

INTRODUCTION
NHL: non-Hodgkins lymphoma DLBCL: diffuse large B cell lymphoma, a subtype of NHL CD20 antigen: transmembrane protein expressed specically on B cells, but not found on pre B cells or stem cells Chemoimmunotherapy: use of chemotherapy combined with an immune therapy, such as a monoclonal antibody

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

Non-Hodgkins lymphoma (NHL) is the fth most frequently diagnosed cancer in the United States. NHL accounts for 4% of all new cancer cases and 3% of all cancer-related deaths in both men and women (1). It is estimated that in 2007 there will be 63,191 new NHL diagnoses and 18,660 NHL-related deaths. Approximately 85% to 90% of all NHL cases in the United States and Western Europe are of B cell origin. Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma are the most common NHL subtypes, accounting for about 31% and 22%, respectively, of new NHL cases (2). Data from the Surveillance, Epidemiology and End Results (SEER) program show that although the incidence of NHL continues to rise in the United States, there has been a signicant decline in NHL-related mortality over the past decade. From 1991 through 2003, the most recent period for which data are available, the incidence of NHL rose at a rate of 0.4% per year according to jointpoint regression analysis (3). From 1991 through 1997, mortality also rose at an annualized rate of 1.6%. However, from 1997 through 2003, mortality rates declined by 2.8% per year. Although throughout this time NHL

therapies continued to be evaluated and rened, it is interesting that the downward shift in NHL mortality coincided with the introduction of rituximab (Rituxan, MabThera) (Figure 1). Rituximab is a chimeric monoclonal IgG1 antibody directed against the CD20 antigen, which is expressed on the surface of nearly all malignant and normal B cells (4, 5). Binding of rituximab to the CD20 antigen induces cell lysis and apoptosis, and it also sensitizes cells to the cytotoxic effects of chemotherapy (57). In 1997, clinical efcacy with rituximab was rst reported in patients with relapsed lowgrade B cell NHL (8). These ndings heralded a new era of immunotherapy for the treatment of B cell lymphomas. Since then, the role of rituximab in the treatment of NHL has expanded across both indolent and aggressive subtypes (9). In low-grade or follicular lymphoma, rituximab has been shown to be effective as a single agent and in combination with chemotherapy (chemoimmunotherapy) in patients with newly diagnosed disease and those with relapsed or refractory disease. Findings from recent randomized clinical trials conrm that in newly diagnosed follicular NHL, the addition of rituximab to frontline

Cisplatin (1978)

Etoposide (1983)

Fludarabine (1991)

Ibritumomab tiuxetan (2002) Tositumomab Rituximab (2003) (1997)

Rate per 100,000*

10

Figure 1 Mortality rates of non-Hodgkins lymphoma (NHL) and new drugs approved in the United States for the treatment of NHL.

NHL Mortality
5

0 1975

1980

1985

1990

1995

2000

2005

*Age adjusted to 2000 US standard population

238

Molina

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

chemotherapy improves response rates as well as progression-free and survival endpoints (1016). Rituximab maintenance therapy can effectively prolong progression-free survival, although additional clinical trials and longer follow-up are needed to ascertain the impact of maintenance therapy on overall survival (1721). In DLBCL, data from three randomized trials conrm that the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like chemotherapy improves both response and survival outcomes in previously untreated patients (2225). The role of maintenance rituximab in DLBCL is less well dened. In patients who have received rituximab and chemotherapy in the frontline setting, it appears unlikely that maintenance rituximab provides any additional clinical benet (24). This review focuses on the development of rituximab-based therapies and novel chemoimmunotherapy regimens in patients with low-grade or follicular NHL and newly
Table 1

diagnosed DLBCL, highlighting key randomized studies and survival outcomes.

CHOP: chemotherapy regimen consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone

RITUXIMAB IN LOW-GRADE OR FOLLICULAR NHL Single-Agent Rituximab

The U.S. Food and Drug Administrations initial approval of rituximab in November 1997 was for the treatment of relapsed or refractory low-grade or follicular NHL. Overall response rates across phase II studies with a standard course of rituximab, 375 mg/m2 weekly for 4 to 8 doses, typically ranged from 40% to 50% (Table 1), including studies that enrolled patients with bulky or advanced disease (2631). Median response duration was 12 months in most patients, though response duration tended to be shorter in patients with bulky or advanced disease. In studies that enrolled newly diagnosed patients, overall response rates of 70%80% with median response durations of 1826 months were seen (3234).

Selected studies of single-agent rituximab in low-grade or follicular NHLa Patients Response (%) CR 49 36 OR 80 72 Time-to-event outcome median PFS = 18 months 5-year RFS = 28% median TTP = 26 months Population follicular NHL, low tumor burden follicular NHL, Grade 1 low-grade or follicular NHL follicular NHL follicular NHL, advanced stage low-grade or follicular NHL, bulky disease low-grade or follicular NHL Rituximab treatment 375 mg/m2 weekly 4 375 mg/m2 weekly 4 (n) 49 36

References Newly diagnosed 32, 33 34

Relapsed/refractory 26, 27 28 29 30 375 mg/m2 weekly 4 375 mg/m2 weekly 4 375 mg/m2 weekly 4 166 70 30 31 6 3 17 3 48 46 47 39 median DR = 11.2 months median DR = 11 months median DR = 5.8 months median DR = 5.9 months

375 mg/m2 weekly 4

31

375 mg/m2 weekly 8

37

14

43

median DR = 13.4+ months

a Abbreviations: NHL, non-Hodgkins lymphoma; CR, complete response; OR, overall response, PFS, progression-free survival; TTP, time to progression; DR duration of response.

www.annualreviews.org Rituximab in Non-Hodgkins Lymphoma

239

Table 2 Randomized trials of chemotherapy with or without rituximab in newly diagnosed follicular NHLa Response (%) References 10, 11 12 14 15, 16 Treatment R-CVP CVP R-CHOP CHOP R-MCP MCP R-CHVP-IFN CHVP-IFN Patients (n) 162 159 223 205 105 96 175 183 CR/CRub 41 10 20a 17a 50 25 79 63 OR 81 57 96 90 92 75 84 73 Overall survival 4-year 2-year 4-year 3.5-year 83% 77% 95% 90% 87% 74% 91% 84% p 0.029 0.016 0.0096 0.029

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

a Abbreviations: R = rituximab; CVP = cyclophosphamide, vincristine, prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; MCP = mitoxantrone, chlorambucil, prednisolone; CVHP-IFN = cyclophosphamide, doxorubicin, etoposide, prednisone, plus -interferon; CR/CRu = complete response/complete response unconrmed; OR = overall response. b Patients meeting CR criteria without conrmed negative bone marrow biopsy were dened as partial responders instead of CRu.

Chemoimmunotherapy
Long-term follow-up has found a signicant improvement in overall survival with the addition of rituximab to chemotherapy across four randomized trials enrolling patients with newly diagnosed advanced follicular lymphoma (Table 2) (1016). Marcus et al. (10, 11) recently reported that adding rituximab to CVP (cyclophosphamide, vincristine, prednisone) chemotherapy increased both complete and overall response rates and more than doubled the median time to disease progression (34 months versus 15 months) compared to CVP alone ( p < 0.0001). The four-year disease-free survival rate for patients with a complete response (CR or CRu) was 54% with R-CVP compared to 17% with CVP ( p = 0.0001). The addition of rituximab also signicantly improved overall survival. With a median follow-up time of 53 months, four-year estimated overall survival rates were 83% with R-CVP versus 77% with CVP ( p = 0.029). Hiddemann et al. (12) found that the addition of rituximab to CHOP resulted in a signicantly higher overall response rate 96% versus 90% with CHOP alone ( p = 0.011). Time to treatment failure (TTF) was also longer with R-CHOP. Although the meMolina

CR/CRu: complete response/complete response unconrmed

dian follow-up time of 18 months was relatively short, there was a statistical difference in TTF, with the median not yet reached with R-CHOP compared to 2.6 years for CHOP alone ( p < 0.001). Only 28 treatment failures occurred with R-CHOP compared to 61 with CHOP. Estimated 2-year overall survival rates were 95% with R-CHOP and 90% with CHOP ( p = 0.016), with 6 deaths in the R-CHOP group compared to 17 deaths in the CHOP group within the rst 3 years. The addition of rituximab to MCP (mitoxantrone, chlorambucil, prednisolone) chemotherapy also improved response rates and survival times (13, 14). In patients with advanced follicular lymphoma, the overall response rate with R-MCP was 92% compared to 75% with MCP ( p = 0.0004), with complete response rates of 50% and 25%, respectively ( p = 0.0009). With a median followup time of 47 months, R-MCP resulted in longer progression-free survival ( p < 0.0001), with an estimated four-year progression-free survival rate of 71% versus 41% with MCP. Overall survival also favored R-MCP, with estimated four-year overall survival rates of 87% versus 74% ( p = 0.0096). Foussard and colleagues (15, 16) found that the addition of rituximab to

240

a combination regimen of CHVP-IFN (cyclophosphamide, doxorubicin, etoposide, prednisone, followed by 2-interferon) also improved response and survival outcomes. For R-CHVP-IFN the overall response rate was 84% versus 73% for CHVP-IFN ( p = 0.004). With a median follow-up time of 3.5 years, event-free survival and overall survival outcomes also signicantly favored the addition of rituximab. Comparative estimated event-free survival rates were 81% versus 62% ( p = 0.002), and overall survival rates were 91% versus 84% ( p = 0.029). An ongoing randomized trial is comparing rituximab alone to chemotherapy with CNOP (cyclophosphamide, mitoxantrone, vincristine, and prednisone) and chemoimmunotherapy with CNOP plus rituximab in patients with newly diagnosed indolent lymphoma. Preliminary results from 195 patients indicate no statistical difference in either overall response rates (85% for rituximab, 83% for CNOP, and 90% for R-CNOP) or two-year overall survival rates (87%, 84%, and 78%, respectively) (35). Further details of this study and additional follow-up time are needed to more fully evaluate these results. An overall survival benet from the addition of rituximab to chemotherapy in patients with indolent NHL was also identied in a meta-analysis conducted by the Cochrane Hematological Malignancies Group (36). Data from six randomized clinical trials of chemotherapy with or without rituximab in patients with newly diagnosed or relapsed/refractory indolent or mantle cell lymphoma were included (10, 12, 13, 35, 37, 38). Overall survival, the primary study parameter, was evaluated using data from 994 patients enrolled across ve trials. This analysis found that adding rituximab to chemotherapy signicantly improved survival compared to chemotherapy alone, with a hazard ratio of 0.61 (95% CI: 0.470.80).

Rituximab Maintenance
The use of maintenance rituximab can improve disease control in patients with indolent

or follicular NHL. Results of randomized studies suggest clinical benet from several different rituximab extended-dosing and maintenance strategies following singleagent rituximab therapy, chemotherapy, or chemoimmunotherapy. In a phase III trial, follicular NHL patients with responding or stable disease following a standard course of rituximab were randomized either to maintenance rituximab, given as a single dose at week 12 and months 5, 7, and 9, or to observation (17). Among 151 patients, maintenance rituximab produced signicant improvements in both response duration, 36 months versus 16 months ( p = 0.0039), and event-free survival time, 23 months versus 12 months ( p = 0.02), compared to observation. Hainsworth et al. (18) evaluated maintenance rituximab in 90 patients with indolent NHL who had initially responsive or stable disease. A standard course of rituximab, repeated at six-month intervals, was compared to retreatment with rituximab at the time of disease progression. The use of maintenance rituximab increased the overall response rate from 39% following initial therapy to 52%. Time to disease progression was 31 months with maintenance rituximab versus 7 months without ( p = 0.007). Hochster et al. evaluated maintenance rituximab following chemotherapy in patients with newly diagnosed advanced follicular NHL (19). This phase III trial enrolled 237 patients with responding or stable disease following CVP chemotherapy, who were randomized either to maintenance rituximab, given as four weekly doses every six months for two years, or to observation. Both time to disease progression and overall survival were signicantly prolonged with maintenance rituximab (Table 3). Comparative four-year progression-free survival rates were 56% versus 33% ( p < 0.0001), and four-year overall survival rates were 88% versus 72% ( p = 0.03). Other investigators reported that maintenance rituximab improved response and survival outcomes in patients with relapsed
241

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

www.annualreviews.org Rituximab in Non-Hodgkins Lymphoma

Table 3 Randomized trials of maintenance rituximab following chemotherapy or chemoimmunotherapy in low-grade or follicular NHLa Treatment References 19 20 21 Population newly diagnosed advanced stage follicular NHL relapsed/refractory follicular NHL relapsed/refractory follicular and mantle cell lymphoma Initial CVP R-CHOP CHOP R-FCM FCM Maintenance R Obs. R Obs. R Obs. Patients (n) 237 334 176 Overall survival 4-year 3-year 3-year 88% 72% 85% 77% 77% 57% p 0.03 0.011 0.10

a Abbreviations: R = rituximab; CVP = cyclophosphamide, vincristine, prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; FCM = udarabine, cyclophosphamide, mitoxantrone; Obs. = observation.

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

or refractory follicular NHL initially treated with CHOP alone or CHOP with rituximab (Table 3) (20). Following an initial randomization to either CHOP or R-CHOP, responding patients underwent a second randomization either to maintenance rituximab, given as a single dose every three months for two years, or to observation. With initial therapy, the addition of rituximab to CHOP signicantly improved both the overall response rate, 85% versus 72% ( p < 0.001), and the median progression-free survival time, 33 months versus 20 months ( p < 0.001). With a median follow-up time of 33 months from the second randomization, median progression-free survival was more than three times longer with rituximab maintenance 52 months compared to 15 months with observation ( p < 0.0001). Progression-free survival improved with maintenance rituximab following both CHOP and R-CHOP. Overall survival also improved with maintenance rituximab; three-year overall survival rates (from second randomization) were 85% versus 77% ( p = 0.011). Forstpointner et al. evaluated maintenance rituximab following FCM (udarabine, cyclophosphamide, mitoxantrone) chemotherapy with or without rituximab in patients with relapsed or refractory follicular or mantle cell lymphoma (21). The initial treatment randomization of R-FCM versus FCM was stopped after the rst 147 patients upon recognition of a signicantly higher overall
242 Molina

response rate, 79% versus 58% ( p = 0.01), and longer progression-free survival ( p = 0.014) with R-FCM (37). All patients enrolled thereafter received R-FCM as initial therapy. Responding patients underwent a second randomization either to maintenance rituximab, given as four weekly doses at three months and nine months, or to observation. Duration of response was signicantly longer with maintenance rituximab. With a median follow-up time of 26 months, median time to disease progression had not been reached in the maintenance group compared to 17 months for observation ( p < 0.001). Overall survival rates at three years were 77% with maintenance rituximab and 57% without, although this difference did not reach statistical signicance. Emerging evidence suggests a potential role for maintenance rituximab in patients with low-grade or follicular NHL. However, in the above studies, very different maintenance rituximab strategies were used, and an optimal rituximab maintenance schedule and duration of treatment remain to be dened. Different frontline modalities were also used, and results of these studies need to be interpreted in light of evolving standards of care.

RITUXIMAB IN AGGRESSIVE NHL

In patients with newly diagnosed DLBCL, the addition of rituximab to CHOP or CHOPlike chemotherapy has been shown to improve

Table 4

Randomized trials of chemotherapy with or without rituximab in newly diagnosed DLBCLa Response (%) Population newly diagnosed advanced DLBCL, age 6080 years newly diagnosed DLBCL, age 60 years newly diagnosed, good prognosis DLBCL, age 1860 years Treatment R-CHOP CHOP Patients (n) 399 CR/CRu 75 63 OR 82 69 Overall survival 5-year 58% 45%

References 22, 23

p 0.0073

24

R-CHOP CHOP R versus Obs. R-CHOP-likec CHOP-likec

546

77 76 86 68

3-yearb

67% 58% 93% 84%

0.05

25

823

3-year

0.0001

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

a DLBCL = diffuse large B cell lymphoma; R = rituximab; Obs. = observation; CR/CRu = complete response/complete response unconrmed; OR = overall response. b Secondary analysis of induction therapy without maintenance rituximab. c CHOP-like chemotherapy included CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin), and PMitCEMO (mitoxantrone, cyclophosphamide, etoposide, vincristine, bleomycin, prednisone).

response and survival outcomes across three randomized trials (Table 4). These data were used to support an extension of rituximabs approved indications by the U.S. Food and Drug Administration in 2006. In the seminal study coordinated by the Groupe dEtudes des Lymphomes de lAdulte (GELA), the addition of rituximab to CHOP signicantly improved response rate and survival times in newly diagnosed DLBCL patients aged 6080 years (22). The overall response rate with R-CHOP was 82% compared to 69% with CHOP alone ( p = 0.005). With longterm follow-up, progression-free survival outcomes continued to signicantly favor R-CHOP ( p < 00001), with comparative ve-year progression-free survival rates of 54% versus 30% (23). Overall survival was also longer with R-CHOP, with comparative 5-year overall survival rates of 58% versus 45% ( p = 0.0073). Another trial has also compared R-CHOP to CHOP in newly diagnosed DLBCL patients aged 60 years (24). This phase III US Intergroup trial differed in design from the GELA trial in that patients who responded to initial therapy underwent a sec-

ond randomization to maintenance rituximab or observation. In contrast to the GELA trial, there was no difference in overall response following initial therapy, with rates of 77% and 76% with R-CHOP and CHOP, respectively. The lack of difference in response rates between the two study arms of the US Intergroup trial may be related to the requirement for the use of fewer cycles of chemotherapy, fewer rituximab treatments, and a different schedule of rituximab administration, as well as enrollment of a higher perecntage of high-risk patients compard to the GELA trial. Another potential contibuting factor was the requirement for conrmation of responses at four weeks or later and the timing of second randomization within that period. Survival analyses from this study were relatively complex. However, with a median follow-up time of 3.5 years, the estimated three-year progression-free survival rate was longer for R-CHOP compared to CHOP induction, 53% versus 46% ( p = 0.04). Because of the potential confounding effects of maintenance rituximab on the induction comparison, an inverse probability-weighted statistical analysis was performed to compare
243

www.annualreviews.org Rituximab in Non-Hodgkins Lymphoma

CLL: chronic lymphocytic leukemia

induction regimens in the absence of maintenance rituximab. In this secondary analysis, overall survival was signicantly longer with R-CHOP; the estimated three-year overall survival rate was 67% with R-CHOP compared to 58% with CHOP alone ( p = 0.05). This trial also evaluated maintenance rituximab following either CHOP or R-CHOP. There was a signicant difference in the effect of maintenance therapy according to which induction therapy was given; maintenance rituximab prolonged failure-free survival following CHOP but not R-CHOP ( p = 0.05). After the second randomization, estimated two-year failure-free survival rates were as follows: 79% for R-CHOP plus maintenance, 77% for R-CHOP alone, 74% for CHOP plus maintenance, and 45% for CHOP alone. Overall, these ndings indicate that the use of rituximab either as part of initial therapy or as maintenance therapy in responding patients signicantly prolongs failure-free survival ( p < 0.001). These ndings further indicate that use of maintenance rituximab following initial chemoimmunotherapy that includes rituximab is unlikely to provide additional benet. In younger patients with good-prognosis DLBCL, response and survival benets from the addition of rituximab to CHOP or CHOP-like chemotherapy have recently been reported (25). This phase III study enrolled newly diagnosed DLBCL patients aged 18 60 with zero or one risk factor according to the age-adjusted International Prognostic Index (IPI) (39). Patients were randomized to receive frontline chemotherapy (one of four regimens selected by the participating institution) with or without rituximab. Most patients (92%) received CHOP or CHOEP (CHOP plus etoposide). Chemotherapy plus rituximab produced a higher rate of CR/CRu than chemotherapy alone, 86% versus 68% ( p < 0.0001). With a median follow-up time of 34 months, patients who received rituximab with chemotherapy had signicantly longer progression-free and overall survival times. Comparative three-year progression-free sur244 Molina

vival estimates were 85% versus 68% ( p < 0.0001), and three-year overall survival estimates were 93% versus 84% ( p = 0.0001). Improved clinical outcomes with the addition of rituximab were seen with both CHOP and CHOEP regimens.

DISCUSSION
Rituximab has become an integral component in the management of many patients with NHL. Treatment guidelines established by the National Comprehensive Cancer Network (NCCN) suggest rituximab-based therapies for patients with follicular NHL and DLBCL, and they indicate that rituximab is an optional component of therapy for other forms of NHL, including chronic lymphocytic leukemia (CLL), marginal zone lymphoma, and mantle cell lymphoma (40). Newer treatment options, and in particular the introduction of rituximab, appear to have improved the long-term prognosis of patients with follicular NHL and DLBCL. Across a series of studies conducted in patients with follicular NHL over the past three decades by the Southwest Oncology Group (SWOG), four-year overall survival estimates have improved from 69% with CHOP alone to 91% with CHOP plus monoclonal antibody therapy ( p < 0.001) (41). Substantial improvements in survival outcomes in patients with follicular NHL have also been reported by the Gruppo Italiano Studio Linfomi (GISL) and these are thought to be related primarily to the use of rituximab in combination with chemotherapy (42). The results of recent phase III randomized trials further support an improving prognosis. In newly diagnosed follicular NHL patients, the combination of rituximab with CVP, CHOP, MCP, and CHVPIFN increases response rates and prolongs progression-free and overall survival times (11, 12, 14, 16). In patients with relapsed or refractory disease, combinations of rituximab with CHOP or FCM have improved response rate and time to disease progression (20, 37).

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

PRIMA
Maintenance Rituximab x 1 every 8 weeks for 24 months
CR/PR

Figure 2 Study design of the PRIMA trial, evaluating maintenance rituximab versus observation following frontline therapy with rituximab combined with one of three chemotherapy regimens in patients with newly diagnosed follicular NHL.

Rituximab x 8 in combination with

CVP x 8 cycles CHOP x 6 cycles FCM x 6 cycles

3-year follow-up

Observation for 24 months

N = 1200 patients
Enrollment: previously untreated stage III/IV follicular NHL (Grade 1, 2, or 3 by World Health Organization (WHO) criteria)

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

Maintenance rituximab can extend response duration and time to disease progression following rituximab monotherapy, chemotherapy, or chemoimmunotherapy (1721). Overall survival benets with maintenance rituximab have been seen in some randomized trials (19, 20), although additional trials and follow-up are needed to conrm a longterm clinical benet. Additional information on the benet of maintenance rituximab following chemoimmunotherapy for patients with previously untreated follicular NHL will be provided by the Primary Rituximab and Maintenance (PRIMA) trial (Figure 2). The trial is coordinated by GELA and is being conducted at sites primarily in Europe and Australia. The primary study endpoint is event-free survival, with response, progression-free survival, and overall survival evaluated as secondary endpoints. Accrual of 1200 patients was recently completed. In patients with DLBCL, the addition of rituximab to CHOP or CHOP-like chemotherapy has improved response and survival outcomes in newly diagnosed patients older than 60 years as well as younger patients with good prognostic features in phase III trials (2225). A population-based analysis conducted in British Columbia supports these ndings, noting a substantial survival benet with the addition of rituximab to CHOP across all age groups (43). The role of maintenance rituximab in patients with DLBCL

is less clear, but it seems unlikely that it will provide any further benet to those who have received rituximab as part of their initial therapy. The improved survival outcomes in DLBCL resulting from the combination of rituximab with CHOP or CHOP-like regimens have prompted an adjustment to the IPI classication to provide a clinically more useful tool (44). The revised International Prognostic Index (R-IPI) maintains the same baseline criteria but identies three prognostic groups: very good (0 risk factors), good (1 or 2 risk factors), and poor (3 to 5 risk factors). Estimated survival rates at four years using RIPI are 94%, 79%, and 53%, respectively. It is interesting that the IPI no longer identies a group with a risk rate below 50%, again suggesting that the prognosis for these patients has improved. An increase in adverse events is always a concern with the addition of any new agent to an established regimen. However, across these phase III trials, the addition of rituximab did not substantially increase adverse event rates in either follicular NHL or DLBCL patients. Although one study reported an increase in severe granulocytopenia with R-CHOP compared to CHOP (12), severe infections were rare and not different between study arms. Most of the trials found the addition of rituximab to chemotherapy to be generally well tolerated, and no clinically meaningful differences in toxicities were seen.
245

www.annualreviews.org Rituximab in Non-Hodgkins Lymphoma

REACH
Enrollment: Active CLL Binet A, B, C Fludarabine sensitive N = 620 patients
The use of rituximab in other B cell NHL subtypes, including CLL, mantle cell lymphoma, and Waldenstrom macroglobulinemia, as well as Hodgkin lymphoma and posttransplant lymphoproliferative disorders, is currently under investigation. Indications of response and potential survival improvements have been seen in phase II studies of rituximab in combination with chemotherapy for patients with newly diagnosed or relapsed/refractory CLL (4548). These ndings are the basis of two ongoing randomized

Figure 3 Study design of the REACH trial, evaluating chemotherapy with or without rituximab for patients with CLL.

Fludarabine Cyclophosphamide Rituximab x 6 courses Fludarabine Cyclophosphamide x 6 courses

clinical trials, one in newly diagnosed CLL patients and the other in patients with relapsed or refractory disease, which will evaluate chemotherapy with udarabine and cyclophosphamide with or without rituximab. Accrual goals have been met for the former study, with completion of accrual for the latter expected by the end of 2007. Both studies use the same design (Figure 3), with progression-free survival as the primary endpoint. Preliminary results are anticipated in 2008.

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

SUMMARY POINTS 1. In newly diagnosed low-grade or follicular NHL, the addition of rituximab to chemotherapy signicantly improves overall response rates and disease control. It may also improve overall survival. 2. In relapsed or refractory low-grade or follicular NHL, the addition of rituximab to chemotherapy signicantly improves overall response rates and disease control. 3. The use of maintenance rituximab in patients with follicular NHL extends progression-free survival, and additional clinical studies are ongoing to assess impact on overall survival. 4. In newly diagnosed DLBCL, the addition of rituximab to CHOP or CHOP-like chemotherapy signicantly improves overall response rates, disease control, and overall survival. 5. In DLBCL patients who have received rituximab as part of frontline chemoimmunotherapy, it is unlikely that maintenance rituximab offers any additional benet.

246

Molina

FUTURE ISSUES 1. The clinical benet of maintenance rituximab therapy following initial treatment with rituximab chemoimmunotherapy combinations in patients with previously untreated follicular lymphoma is not yet well dened. 2. The optimum schedule and duration of maintenance rituximab has yet to be dened. 3. It is not yet known if chronic rituximab therapy may lead to selection of rituximabresistant cells. 4. Will second- and third-generation anti-CD20 antibodies, currently under development, further improve clinical outcomes?
Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

DISCLOSURE STATEMENT
The author was employed at Biogen Idec when this manuscript was submitted for publication. Rituximab was discovered at Idec prior to the Biogen Idec merger. It is currently comarketed as Rituxan by Genentech, Inc. and Biogen Idec in the United States, and as MabThera by Roche outside the United States.

ACKNOWLEDGMENTS
The author thanks Christine Gutheil for editorial assistance. The author also expresses great appreciation to all of the patients who participated in clinical trials of rituximab.

LITERATURE CITED
1. American Cancer Society. 2007. Cancer Facts & Figures 2007. Atlanta, GA: Am. Cancer Soc. 2. The Non-Hodgkins Lymphoma Classication Project. 1997. A clinical evaluation of the International Lymphoma Study Group classication of non-Hodgkins lymphomas. Blood 89:390918 3. Ries LAG, Harkins D, Krapcho M, et al. 2006. SEER Cancer Statistics Review, 1975 2003. Based on Nov. 2005 SEER data submission. Bethesda, MD: Nat. Cancer Inst., http://seer.cancer.gov/csr/1975 2003/ 4. Anderson KC, Bates MP, Slaughenhoupt BL, et al. 1984. Expression of human B cellassociated antigens on leukemias and lymphomas: a model of human B cell differentiation. Blood 63:142433 5. Reff ME, Carner K, Chambers KS, et al. 1994. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:43545 6. Flieger D, Renoth S, Beier I, et al. 2000. Mechanism of cytotoxicity induced by chimeric mouse human monoclonal antibody IDEC-C2B8 in CD20-expressing lymphoma cell lines. Cell Immunol. 204:5563 7. Demidem A, Lam T, Alas S, et al. 1997. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother. Radiopharm. 12:17785 8. Maloney DG, Grillo-Lopez AJ, White CA, et al. 1997. IDEC-C2B8 (rituximab) antiCD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkins lymphoma. Blood 90:218895
www.annualreviews.org Rituximab in Non-Hodgkins Lymphoma 247

9. Cvetkovic RS, Perry CM. 2006. Rituximab: a review of its use in non-Hodgkins lymphoma and chronic lymphocytic leukaemia. Drugs 66:791820 10. Marcus R, Imrie K, Belch A, et al. 2005. CVP chemotherapy plus rituximab compared with CVP as rst-line treatment for advanced follicular lymphoma. Blood 105:141723 11. Marcus RE, Solal-Celigny P, Imrie K, et al. 2006. MabThera (rituximab) plus cyclophosphamide, vincristine and prednisone (CVP) chemotherapy improves survival in previously untreated patients with advanced follicular non-Hodgkins lymphoma. Blood ASH Annu. Meet. Abstr. 108:481 12. Hiddemann W, Kneba M, Dreyling M, et al. 2005. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) signicantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:372532 13. Herold M, Dolken G, Fiedler F, et al. 2003. Randomized phase III study for the treatment of advanced indolent non-Hodgkins lymphomas (NHL) and mantle cell lymphoma: chemotherapy versus chemotherapy plus rituximab. Ann. Hematol. 82:7779 14. Herold M, Haas A, Srock S, et al. 2007. Rituximab added to rst-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology study. J. Clin. Oncol. 25198692 15. Salles GA, Foussard C, Mounier N, et al. 2004. Rituximab added to IFN+CHVP improves the outcome of follicular lymphoma patients with a high tumor burden: rst analysis of the GELA-GOELAMS FL-2000 randomized trial in 359 patients. Blood ASH Annu. Meet. Abstr. 104:160 (Abstr.) 16. Foussard C, Mounier N, Van Hoof A, et al. 2006. Update of the FL2000 randomized trial combining rituximab to CHVP-interferon in follicular lymphoma (FL) patients (pts). J. Clin. Oncol. ASCO Annu. Meet. Proc. 24:7508 (Abstr.) 17. Ghielmini M, Schmitz SF, Cogliatti SB, et al. 2004. Prolonged treatment with rituximab in patients with follicular lymphoma signicantly increases event-free survival and response duration compared with the standard weekly 4 schedule. Blood 103:441623 18. Hainsworth JD, Litchy S, Shaffer DW, et al. 2005. Maximizing therapeutic benet of rituximab: maintenance therapy versus retreatment at progression in patients with indolent non-Hodgkins lymphomaa randomized phase II trial of the Minnie Pearl Cancer Research Network. J. Clin. Oncol. 23:108895 19. Hochster HS, Weller E, Gascoyne RD, et al. 2005. Maintenance rituximab after CVP results in superior clinical outcome in advanced follicular lymphoma (FL): results of the E1496 phase III trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B. Blood ASH Annu. Meet. Abstr. 106:349 (Abstr.) 20. van Oers MH, Klasa R, Marcus RE, et al. 2006. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 108:3295301 21. Forstpointner R, Unterhalt M, Dreyling M, et al. 2006. Maintenance therapy with rituximab leads to a signicant prolongation of response duration after salvage therapy with a combination of rituximab, udarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 108:40038
248 Molina

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

22. Coifer B, LePage E, Briere J, et al. 2002. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346:23542 23. Feugier P, Van Hoof A, Sebban C, et al. 2005. 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 dEtudes des Lymphomes de lAdulte. J. Clin. Oncol. 23:411726 24. Habermann TM, Weller EA, Morrison VA, et al. 2006. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J. Clin. Oncol. 24:312127 25. Pfreundschuh M, Trumper L, Osterborg A, et al. 2006. 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. 7:37991 26. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. 1998. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J. Clin. Oncol. 16:282533 27. McLaughlin P, Hagemeister FB, Grillo-Lopez AJ. 1999. Rituximab in indolent lymphoma: the single-agent pivotal trial. Semin. Oncol. 26(5 Suppl. 14):7987 28. Foran JM, Gupta RK, Cunningham D, et al. 2000. A UK multicentre phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response. Br. J. Haematol. 109:8188 29. Feuring-Buske M, Kneba M, Unterhalt M, et al. 2000. IDEC-C2B8 (rituximab) anti-CD20 antibody treatment in relapsed advanced-stage follicular lymphomas: results of a phase-II study of the German Low-Grade Lymphoma Study Group. Ann. Hematol. 79:493500 30. Davis TA, White CA, Grillo-Lopez AJ, et al. 1999. Single-agent monoclonal antibody efcacy in bulky non-Hodgkins lymphoma: results of a phase II trial of rituximab. J. Clin. Oncol. 17:185157 31. Piro LD, White CA, Grillo-Lopez AJ, et al. 1999. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkins lymphoma. Ann. Oncol. 10:65561 32. Colombat P, Salles G, Brousse N, et al. 2001. Rituximab (anti-CD20 monoclonal antibody) as single rst-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood 97:1016 33. Solal-Celigny P, Salles GA, Brousse N, et al. 2004. Single 4-dose rituximab treatment for low-tumor burden follicular lymphoma: survival analyses with a follow-up of at least 5 years. Blood ASH Annu. Meet. Abstr. 104:585 (Abstr.) 34. Witzig TE, Vukov AM, Habermann TM, et al. 2005. Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkins lymphoma: a phase II trial in the North Central Cancer Treatment Group. J. Clin. Oncol. 23:11038 35. Rivas-Vera S, Baez E, Sobrevilla-Calvo P, et al. 2005. Is rst line single agent rituximab the best treatment for indolent non-Hodgkins lymphoma? Update of a multicentric study comparing rituximab vs CNOP vs rituximab plus CNOP. Blood ASH Annu. Meet. Abstr. 106:2431 (Abstr.) 36. Schulz H, Skoetz N, Bohlius J, et al. 2005. Does combined immunochemotherapy with the monoclonal antibody rituximab improve overall survival in the treatment of patients with indolent non-Hodgkin lymphoma? Preliminary results of a comprehensive meta-analysis. Blood ASH Annu. Meet. Abstr. 106:351 (Abstr.)
www.annualreviews.org Rituximab in Non-Hodgkins Lymphoma 249

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

37. Forstpointner R, Dreyling M, Repp R, et al. 2004. The addition of rituximab to a combination of udarabine, cyclophosphamide, mitoxantrone (FCM) signicantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104:306471 38. Lenz G, Dreyling M, Hoster E, et al. 2005. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone signicantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J. Clin. Oncol. 23:198492 39. The International Non-Hodgkins Lymphoma Prognostic Factors Project. 1993. A predictive model for aggressive non-Hodgkins lymphoma. N. Engl. J. Med. 329:98794 40. National Comprehensive Cancer Network, Inc. 2007. NCCN clinical practice guidelines in oncologyVersion 1.2007. Non-Hodgkins lymphomas. http://www.nccn.org/ professionals/physician gls/PDF/nhl.pdf 41. Fisher RI, LeBlanc M, Press OW, et al. 2005. New treatment options have changed the survival of patients with follicular lymphoma. J. Clin. Oncol. 23:844752 42. Sacchi S, Pozzi S, Marcheselli L, et al. 2007. Introduction of rituximab in front-line and salvage therapies has improved outcome of advanced-stage follicular lymphoma patients. Cancer 109:207782 43. Sehn LH, Donaldson J, Chhanabhai M, et al. 2005. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J. Clin. Oncol. 23:502733 44. Sehn LH, Berry B, Chhanabhai M, et al. 2007. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 109:185761 45. Byrd JC, Rai K, Peterson BL, et al. 2005. Addition of rituximab to udarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 105:4953 46. Keating MJ, OBrien S, Albitar M, et al. 2005. Early results of a chemoimmunotherapy regimen of udarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J. Clin. Oncol. 23:407988 47. Wierda W, OBrien S, Wen S, et al. 2005. Chemoimmunotherapy with udarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J. Clin. Oncol. 23:407078 48. Wierda W, OBrien S, Faderl S, et al. 2006. A retrospective comparison of three sequential groups of patients with recurrent/refractory chronic lymphocytic leukemia treated with udarabine-based regimens. Cancer 106:33745

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

250

Molina

Annual Review of Medicine

Contents
The FDA Critical Path Initiative and Its Inuence on New Drug Development Janet Woodcock and Raymond Woosley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Reversing Advanced Heart Failure by Targeting Ca2+ Cycling David M. Kaye, Masahiko Hoshijima, and Kenneth R. Chien p p p p p p p p p p p p p p p p p p p p p p p p 13 Tissue Factor and Factor VIIa as Therapeutic Targets in Disorders of Hemostasis Ulla Hedner and Mirella Ezban p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Therapy of Marfan Syndrome Daniel P. Judge and Harry C. Dietz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 43 Preeclampsia and Angiogenic Imbalance Sharon Maynard, Franklin H. Epstein, and S. Ananth Karumanchi p p p p p p p p p p p p p p p p p 61 Management of Lipids in the Prevention of Cardiovascular Events Helene Glassberg and Daniel J. Rader p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 79 Genetic Susceptibility to Type 2 Diabetes and Implications for Antidiabetic Therapy Allan F. Moore and Jose C. Florez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 95 Array-Based DNA Diagnostics: Let the Revolution Begin Arthur L. Beaudet and John W. Belmont p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p113 Inherited Mitochondrial Diseases of DNA Replication William C. Copeland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p131 Childhood Obesity: Adrift in the Limbic Triangle Michele L. Mietus-Snyder and Robert H. Lustig p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p147 Expanded Newborn Screening: Implications for Genomic Medicine Linda L. McCabe and Edward R.B. McCabe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p163 Is Human Hibernation Possible? Cheng Chi Lee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p177 Advance Directives Linda L. Emanuel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p187

Volume 59, 2008

Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

Genetic Determinants of Aggressive Breast Cancer Alejandra C. Ventura and Soa D. Merajver p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p199 A Role for JAK2 Mutations in Myeloproliferative Diseases Kelly J. Morgan and D. Gary Gilliland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p213 Appropriate Use of Cervical Cancer Vaccine Gregory D. Zimet, Marcia L. Shew, and Jessica A. Kahn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p223 A Decade of Rituximab: Improving Survival Outcomes in Non-Hodgkins Lymphoma Arturo Molina p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p237
Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

Nanotechnology and Cancer James R. Heath and Mark E. Davis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p251 Cancer Epigenetics: Modications, Screening, and Therapy Einav Nili Gal-Yam, Yoshimasa Saito, Gerda Egger, and Peter A. Jones p p p p p p p p p p p p267 T Cells and NKT Cells in the Pathogenesis of Asthma Everett H. Meyer, Rosemarie H. DeKruyff, and Dale T. Umetsu p p p p p p p p p p p p p p p p p p p p281 Complement Regulatory Genes and Hemolytic Uremic Syndromes David Kavanagh, Anna Richards, and John Atkinson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p293 Mesenchymal Stem Cells in Acute Kidney Injury Benjamin D. Humphreys and Joseph V. Bonventre p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p311 Asthma Genetics: From Linear to Multifactorial Approaches Stefano Guerra and Fernando D. Martinez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p327 The Effect of Toll-Like Receptors and Toll-Like Receptor Genetics in Human Disease Stavros Garantziotis, John W. Hollingsworth, Aimee K. Zaas, and David A. Schwartz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p343 Advances in Antifungal Therapy Carole A. Sable, Kim M. Strohmaier, and Jeffrey A. Chodakewitz p p p p p p p p p p p p p p p p p p361 Herpes Simplex: Insights on Pathogenesis and Possible Vaccines David M. Koelle and Lawrence Corey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p381 Medical Management of Inuenza Infection Anne Moscona p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p397 Bacterial and Fungal Biolm Infections A. Simon Lynch and Gregory T. Robertson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p415 EGFR Tyrosine Kinase Inhibitors in Lung Cancer: An Evolving Story Lecia V. Sequist and Thomas J. Lynch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p429 Adaptive Treatment Strategies in Chronic Disease Philip W. Lavori and Ree Dawson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p443
vi Contents

Antiretroviral DrugBased Microbicides to Prevent HIV-1 Sexual Transmission Per Johan Klasse, Robin Shattock, and John P. Moore p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p455 The Challenge of Hepatitis C in the HIV-Infected Person David L. Thomas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p473 Hide-and-Seek: The Challenge of Viral Persistence in HIV-1 Infection Luc Geeraert, Gnter Kraus, and Roger J. Pomerantz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p487 Advancements in the Treatment of Epilepsy B.A. Leeman and A.J. Cole p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p503
Annu. Rev. Med. 2008.59:237-250. Downloaded from arjournals.annualreviews.org by Kennesaw State University on 10/06/08. For personal use only.

Indexes Cumulative Index of Contributing Authors, Volumes 5559 p p p p p p p p p p p p p p p p p p p p p p p p525 Cumulative Index of Chapter Titles, Volumes 5559 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p529 Errata An online log of corrections to Annual Review of Medicine articles may be found at http://med.annualreviews.org/errata.shtml

Contents

vii