A Decade of Progress in Lymphoma: Advances and Continuing Challenges

Review

A Decade of Progress in Lymphoma: Advances and Continuing Challenges Christopher R. Flowers,1 James O. Armitage2 Abstract Our ability to manage patients with non-Hodgkin lymphoma and Hodgkin lymphoma has improved dramatically in the past decade. The survival of patients with the two most frequent lymphomas (ie, diffuse large B-cell lymphoma and follicular lymphoma), have improved significantly with the incorporation of rituximab as a standard treatment regimen. New insights into the biology of lymphomas provided by studying patterns of gene expression have improved our ability to classify these diseases. Identifying the treatments most effective with different patterns of gene expression offers the opportunity to further improve treatment outcomes. We now cure most patients with Hodgkin lymphoma, but the past decade has seen advances in our ability to identify patients who are most likely to be cured with less toxic treatment approaches. Unfortunately, our ability to improve the treatment of patients with peripheral T-cell lymphoma has not kept pace with the management of those suffering from B-cell lymphomas. However, better classification systems, improved understanding of the biology of these disorders, and clinical trials aimed specifically at identifying optimal regimens for patients with aggressive peripheral T-cell lymphomas offer hope to improve treatment results over the next decade. Clinical Lymphoma, Myeloma & Leukemia, Vol. 10, No. 6, 414-423, 2010; DOI: 10.3816/CLML.2010.n.0nÈ Keywords: B cell, Disease classification, Rituximab, T cell

Introduction The incidence of lymphoma increased dramatically from the 1970s until the mid 1990s largely as a result of rises in the incidence of non-Hodgkin lymphoma (NHL) during this period. The American Cancer Society estimates that 65,540 new cases of NHL and 8490 new cases of Hodgkin lymphoma (HL) will occur in 2010.1 Collectively, the lymphomas are the fifth most common cancer type and the sixth most common cause of cancer deaths in the United States, and are expected to account for 21,530 deaths in 2010.1 Because of the rapid increase in the incidence over the past several decades and the lack of effective prevention for lymphoma, development of novel therapies and improved management strategies are clinical priorities. Patients with lymphoma have benefited greatly from decades of basic science and clinical research, leading to approval of several new chemical entities for lymphoma treatment from 2000 to 2010 and numerous innovative strategies for determining lymphoma subtype, prognosis, and response to therapy. Here, we describe 5 key advances in lymphoma patient 1Winship

Cancer Institute, Emory University, Atlanta, GA of Nebraska medical center, Omaha, NE

2University

Submitted: Oct 14, 2010; Accepted: Nov 14, 2010 Address for correspondence: Christopher R. Flowers, MD, MS, Director, Lymphoma Program, Winship Cancer Institute, Emory University, 1365 Clifton Rd, NE Bldg B, Ste 4302, Atlanta, GA 30322 Fax: 404-778-5520; e-mail: [email protected]

management over the past decade and 5 corresponding current and future challenges to be addressed in the decade to come.

Improved Classification of Lymphoma Subtypes The lymphomas are comprised of many biologically distinct subtypes that can be distinguished from one another by histology and clinical behavior. Historically, the NHLs in particular have been difficult to diagnosis given their varying incidence patterns, different subtypes, clinical presentation, and the lack of a comprehensive classification system. The classification of lymphoid neoplasms has been updated several times since the 1940s. Lymphomas diagnosed from 1973 through 1977 were classified according to the Manual of Tumor Nomenclature and Coding.2 Beginning in 1978, the more detailed schema of the International Classification of Diseases for Oncology3 was adopted to code all lymphomas and other cancers registered by the National Cancer Institute’s Surveillance, Epidemiology, and End Results program. In 1994, the Revised European-American Lymphoma (REAL) classification was adopted incorporating morphology, immunophenotype, genetic, and clinical features into disease subtype definitions.4 In 2001, the World Health Organization (WHO) classification was introduced building on the REAL classification and the French-American-British classification systems.5 With the introduction of immunophenotyping, genotyping, and advances in pathologic classification systems from the Working Formulation to the updated Kiel classification, the REAL classification, and finally,

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the WHO classification, the ability to diagnose lymphoma subtypes improved and provided a foundation for understanding the biologic and clinical variability across the lymphomas.6 In particular, the 2001 WHO classification system was adopted broadly for use by hematopathologists, clinicians, and investigators supplying a common terminology for examining emerging genetic and biologic data on lymphomas along with information on clinical behavior. The WHO classification system now defines distinct clinical entities that provide a basis for the design of subtype-specific management strategies and clinical trials of novel therapies. In 2008, the 4th edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues was published, building upon the 2001 edition (Table 1). This revision refined some categories of lymphoma subtypes and defined new clinical/pathologic entities. These modifications highlight the growing appreciation over the last decade of the heterogeneity across the NHLs and the overlap between disease states such as primary mediastinal large B-cell lymphoma (PMBL) and nodular sclerosis classic HL involving the mediastinum. For instance, lymphomas that occur with these overlapping clinical features, formerly called “grey zone” lymphomas, are now known to have gene expression profiles similar to both PMBL and classical HL.7,8 In the 2008 WHO classification system, provisional categories were created for B-cell neoplasm’s with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical HL and for B-cell lymphomas with features intermediate between DLBCL and Burkitt lymphoma (BL).9 This latter group of lymphomas has a germinal center phenotype akin to BL but exhibit atypical cytologic features for BL.10,11 Although creating such seemingly indistinct lymphoma subtypes appears to contradict efforts to provide increasingly specific classification systems, such clinical entities provide common definitions that can be used to establish specific treatment strategies for these diagnostically challenging cases of DLBCL. Additionally, the Fourth edition of the WHO classification of lymphoid malignancies eliminated diagnostic categories such as atypical BL and subcategories of follicular lymphoma (where the separation of grades 1 and 2 was not associated with clinical differences long term outcomes). Moreover, stratification of follicular lymphoma into grades 1-3, according to the proportion of centroblasts, had poor interobserver and intraobserver reproducibility and distinguishing between follicular lymphoma (FL) grades 3A and 3B based on the absence of centrocytes in the latter category was fraught with additional challenges. To address these issues, the 2008 WHO classification groups cases with few centroblasts as “FL grade 1 to 2 (low grade)” and removed the subgroups for FL grade 3A and 3B, to promote the pathologist to classify cases grade 3 FL with diffuse growth patterns (common in the former grade 3B) as DLBCL. This is appropriate because emerging data indicate that FL grade 3B is related to DLBCL at the molecular level.10-12 As these examples illustrate, the improvements in classification of lymphoid malignancies over the last decade have established categories of lymphomas with distinct biologic and clinical behavior that provide a solid foundation for defining subtype-specific management strategies.

Challenges Although the WHO classification system utilizes immunophenotyping by flow cytometry, cytogenetics, and other modern

Table 1 World Health Organization Classification of Lymphomas B-Cell Lymphomas Precursor B lymphoblastic lymphoma/leukemia

Precursor B-Cell

Chronic lymphocytic leukemia/ small lymphocytic lymphoma Lymphoplasmacytic lymphoma Splenic marginal zone lymphoma Extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT-lymphoma)

Mature B-Cell

Nodal marginal zone B-cell lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma B-Cell Proliferations of Uncertain Malignant Potential

Burkitt lymphoma/leukemia Lymphomatoid granulomatosis Posttransplant lymphoproliferative disorders, polymorphic

T-Cell and NK Cell Neoplasms Precursor T-Cell

Precursor T-cell lymphoblastic leukemia/lymphoma Blastic NK cell lymphoma Adult T-cell leukemia/lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma

Mature T-Cell and NK Cell

Mycosis fungoides Sézary syndrome Primary cutaneous anaplastic large cell lymphoma Peripheral T-cell lymphoma, unspecified Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma

Abbreviations: MALT = mucosa-associated lymphoid tissue; NK = natural killer

pathologic tools to designate particular lymphoma subtypes, in some instances these designations lag behind available technologies. For instance, despite the segregation of DLBCL into specific subtypes defined by the 2008 classification system, there remains a large number of DLBCL cases classified as DLBCL, not otherwise specified (NOS). Studies performing gene expression profiling of DLBCL have defined biologically distinct and prognostically significant molecular subgroups of DLBCL.13 One group has a gene expression pattern similar to normal germinal center B cells (GCB-like DLBCL), whereas another has a contrasting gene expression profile similar to activated B cells (ABC-like DLBCL). As mentioned above, another DLBCL subtype, PMBL,

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A Decade of Progress in Lymphoma has a gene expression signature that significantly overlaps with HL cell lines.7,14 Additional gene expression studies have upheld these findings and expanded on them.7,15 However, despite their biologic and prognostic significance (discussed below) the GBClike and ABC-like subtypes were not formally incorporated into the 2008 WHO classification system based on the limited availability of gene expression profiling as a routine diagnostic test, the imperfect correlation between early immunohistochemical surrogate markers and genomic studies, and the lack of clinical data at that time demonstrating that subtyping could be used to direct therapy.10 Because gene expression profiling was not expected to be broadly implemented in community practices, immunohistochemistry staining algorithms have been developed and validated to classify DLBCL into GCB and ABC subtypes. An initial algorithm used CD20, CD10, Bcl-6, and MUM1 to distinguish GCB and non-GCB subtypes (mostly ABC), and reproduced the gene expression results in 88% of non-GCB cases and 71% of GCB cases.16 More recently, immunohistochemistry stains for GCET1, CD10, BCL6, MUM1, and FOXP1 have been used to derive a new algorithm with 93% concordance with gene expression profiling.17 These strategies for DLBCL classification along with new clinical trials evaluating subtype-specific treatments for DLBCL variants, suggest that the barrier to incorporating DLBCL biologic subtypes into the WHO classification system are being addressed. However, it remains to be seen how the next revision of the WHO classification will view gene expression profiling and immunohistochemical algorithms for classifying DLBCL and other lymphomas. Additional challenges in the future classification of lymphomas include: identifying and defining early/precursor lymphoid processes like circulating clonal memory B cells with t(14;18) and monoclonal B-cell lymphocytosis some of which may progress to clinically significant disease whereas others will not develop malignant behavior,18,19 and segregating other aggressive lymphomas (notably peripheral T-cell lymphoma, NOS) into biologically distinct entities that can be addressed by subtype-targeted therapeutic approaches.

Immunotherapy Therapeutic advances in the treatment of B-cell NHL have significantly improved remission duration and overall survival (OS). In the last decade, these benefits have largely arisen as a result of the integration of immunotherapy into the management of B-cell lymphomas. Because most cytotoxic chemotherapy agents and regimens act most effectively on actively dividing lymphoma cells, they require ongoing cell division during the period of drug exposure. Because indolent B-cell NHLs often are not rapidly proliferating, cytotoxic therapies may not eradicate all cancer cells, which may contribute to disease relapse.20 On the other hand, more aggressive lymphomas may have higher rates of developing both genetic and epigenetic changes that may allow such cells to evade standard chemotherapy, but could still render them to be susceptible to immunotherapy-based approaches. Moreover, lymphomas are ideally suited to immunotherapy, because B-cell lymphomas are able to function as antigen presenting cells. Immunotherapy strategies have included the use of “naked” monoclonal antibodies, radio-labeled antibodies, and antibodies linked to chemotherapy or toxins, vaccines, and cellular therapies.

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The widespread utilization and benefits of rituximab, a monoclonal antibody directed at the CD20 antigen, are well known to the readership of this journal and will be only covered superficially here. Recent more complete reviews (among many others) of the benefits of monoclonal antibodies have been published.21-24 Because CD20 is a cell-surface protein that is present on most malignant B-cell lymphomas, it creates an ideal target for lymphoma-specific therapy. Several mechanisms of action have been suggested for rituximab including: compliment mediated cytotoxicity, direct apoptotic effects, and synergistic effects with chemotherapy agents. Rituximab also may interfere with intracellular signaling pathways sensitizing lymphoma cells to chemotherapy. In the open-label, multicenter, pivotal clinical study, leading to drug approval in 1997, rituximab alone was administered to 166 patients with low-grade or follicular, CD20+ B-cell NHL that had relapsed or was not responsive to previous therapy.25 The overall response rate (ORR) reported was 48% (6% complete responses [CRs] and 42% partial responses). The median time to onset of response was 50 days, the median time to progression (TTP) was 9 months, and the median duration of response was 11 months. Given the benefits of rituximab as a single agent, several groups embarked upon investigations evaluating rituximab in combination with chemotherapy and as maintenance therapy. These approaches were based upon significant single-agent activity, the modest side effect profile, and a mechanism of action that permitted chronic administration and combination. Other early rituximab clinical studies included an expanded-dose regimen (weekly doses for 8 weeks); treatment of bulky low-grade lymphomas; treatment of chronic lymphocytic leukemia (CLL); retreatment of subjects who previously responded to rituximab; and rituximab in combination with chemotherapy across a variety of B-cell malignancies.26-35 When combined with chemotherapy, rituximab increases response rates, duration of remission, and survival compared with chemotherapy alone,33,35-39 but the particular benefit and the magnitude of benefit vary by lymphoma subtype. In addition to an improved cure rate in DLBCL with chemotherapy rituximab combinations,33 combination chemo-immunotherapy strategies appear to have improved OS over time for patients with FL.40,41 In one trial, previously untreated patients with advancedstage follicular lymphoma were randomly assigned to receive either 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) plus rituximab (R-CVP; n = 162) or CVP (n = 159). Overall and CR rates were 81% and 41% in the R-CVP arm and 57% and 10% in the CVP arm (P < .0001). At a median follow-up of 30 months, patients treated with R-CVP had a significantly prolonged TTP (median, 32 months vs. 15 months; P < .0001). Median time to treatment failure was 27 months and 7 months for patients receiving R-CVP and CVP, respectively (P < .0001). In another trial of patients with low-grade B-cell NHL or FL (n = 40) who received 6 infusions of rituximab in combination with 6 doses of the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) the ORR was 95% (CR rate, 55%).42 Overall response rate and CR/unconfirmed complete response (CRu) improved 100% and 87%, respectively, with additional follow-up.43 In a subset of 18 patients, the bcl-2 translocation [t(14;18)] was initially positive in 8 patients and 7 of these patients had CR and converted

Christopher R. Flowers, James O. Armitage to become polymerase chain reaction negative.42 The conversion of bcl-2 from positive to negative indicates possible clearing of minimal residual disease not previously demonstrated by CHOP chemotherapy alone. Long-term follow-up of these patients demonstrated a median TTP of 82.3 months; 3 of the 7 patients had sustained the molecular remission.43 In a randomized clinical trial, the German Low-Grade Lymphoma Study Group has shown that when compared with CHOP alone (n = 205), the R-CHOP combination (n = 223) provides statistically significant improvements in ORR (96% vs. 90%; P = .011), duration of remission (P = .001), and OS (P = .016). Published data from the Southwest Oncology Group show improvements in OS with each succeeding regimen developed for FL with 4-year estimate of OS for CHOP regimens of 69%, 79% for ProMACE-MOPP (procarbazine/methotrexate/doxorubicin/cyclophosphamide/etoposide and nitrogen mustard/vincristine/procarbazine/prednisone) and 91% for the CHOP plus monoclonal antibody regimens (P < .001).41 The addition of rituximab to chemotherapy therapy also has demonstrated clear benefits in mantle cell lymphoma, DLBCL, and CLL (discussed below).33,35,38,39,44-46 In most of these studies, the addition of rituximab was generally associated with limited additional toxicity with the most frequent adverse events being mild to moderate, infusion-related toxicities that occurred most commonly during the first rituximab infusion.33,36,40,47

Challenges Although rituximab and rituximab plus chemotherapy regimens have revolutionized treatment strategies for patients with B-cell lymphomas, to date, the precise mechanism of action of rituximab in each lymphoma subtype, and the reasons for clinical benefits are not well understood. CD20 is involved in many cellular signaling events including proliferation, activation, differentiation, and apoptosis upon cross-linking. Although rituximab can induce complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and apoptosis via a direct effect as mentioned above, effects on cell-signaling pathways and the modulation of apoptotic and antiapoptotic mediators are gaining increasing importance in understanding the mechanism of action of rituximab. Although the relative importance of each of these mechanisms in vivo is largely unknown and the development of the above combination chemoimmunotherapy regimens NHL were predominantly empirical, modifications of cellular signaling pathways by rituximab appear to be important when it is used in combination with chemotherapy. Rituximab causes in vitro growth arrest and sensitizes lymphoma cells to the cytotoxic effect of doxorubicin48 via negative regulation of the NF-κB and ERK1/2 MAPK signal transduction pathways and reduces the expression of their common downstream antiapoptotic gene product Bcl-XL.49-52 Improved understanding of these signaling mechanisms in patients receiving initial rituximab therapy and patients who develop rituximab-refractory disease is necessary to improve our application of rituximab-based treatment strategies, in particular, for relapsed patients. Rituximab has been joined by alemtuzumab and ofatumumab as approved single-agent therapies and by several other antibodies aimed at B-cell targets in clinical trials including veltuzumab, GA101, AME-133 (CD20), epratuzumab (CD22), lumiliximab

Table 2 New Therapeutic Antibodies for Lymphoma Antibody

Target

Ofatumumab

CD20

Veltuzumab

CD20

Epratuzumab

CD22

Lumiliximab

CD23

Galiximab

CD80

Dacetuzumab

CD40

Mapatumumab

TRAIL

Lexatumumab

TRAIL

SGN-35

CD30

Abbreviation: TRAIL = tumor necrosis factor–related apoptosis-inducing ligand

(CD23), galiximab (CD80), dacetuzumab (CD40), mapatumumab, lexatumumab (TRAIL [tumor necrosis factor–related apoptosisinducing ligand]). Moreover, antibody therapies for peripheral T-cell lymphoma (PTCL) and HL are emerging as are approaches to improve antibody therapy such as conjugation with radioisotopes, chemotherapy agents, or toxins (Table 2). The extent to which adding a monoclonal antibody to chemotherapy is a class effect that will be observed with other antibodies will remain unknown until randomized trials comparing rituximab to other anti-CD20 antibodies in chemotherapy combinations are performed. In addition, defining the mechanisms of action and resistance for emerging antibody therapies across lymphoma subtypes will become increasingly important as we attempt to select among antibodies and antibody-based regimens in the future. Idiotype Vaccines. Although most cancers express major histocompatibility complex class I molecules on their surface, each B-cell lymphoma expresses a tumor-specific immunoglobulin molecule on its surface, referred to as an idiotype (Id).53,54 Since 1982, it has been recognized that lymphoma patients treated with monoclonal antibodies directed against the tumor Id had significant tumor regressions, suggesting that Id of B-cell lymphomas could be used as a target for treatment.55 The efficacy of active immunization was demonstrated in animal model in 1987 by Kaminski and colleagues.56 Kwak and colleagues later demonstrated that addition of granulocyte-macrophage colony-stimulating factor to Id linked to keyhole limpet hemocyanin provided a vaccine formulation with substantially improved antilymphoma activity.57 These encouraging results prompted 3, randomized, phase III clinical trials of Id-KLH vaccination after an initial cytoreductive therapy.58-60 One of these studies provided provocative data regarding the correlation of immune and clinical responses and another demonstrated progression-free survival (PFS) benefits in the group that received vaccine compared with patients who did not, but all 3 failed to meet the primary endpoint of the trial. Though lymphoma vaccine therapies have a strong preclinical rationale and have produced some compelling clinical results, active immunotherapy has yet to become a viable approved therapy for lymphomas. Future studies examining active immunotherapy should explore vaccination for lymphoma patients in CR using additional strategies such as

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A Decade of Progress in Lymphoma Figure 1 Overall Survival for Patients With Chronic Lymphocytic Leukemia Receiving Initial Therapy Comparing Initial Anthracycline Versus Chemotherapy Anthracycline as Part of the Initial Treatment

Overall Survival, %

100

Yes No

80

P = .48

60

40 20

0 0

2

4

6

8

10

12

14

16

18

Time, Years

extended vaccination schedules and administration with other immune stimulants to optimize vaccine benefit.

Development of Standard Firstline Regimens for CLL, DLBCL, and Hodgkin Lymphoma Although DLBCL is associated with a median survival of < 1 year in untreated patients,61 advances in the treatment of DLBCL over the past decade have led to excellent outcomes for most patients. Before 2000, CHOP remained the standard initial treatment for DLBCL following its development in the 1970s.62 In the 1980s clinical trials of aggressive combination chemotherapy regimens for intermediate grade NHL reported high CR and survival rates, but these new treatment approaches were more costly, difficult to administer, and had substantial toxicity.63-65 In a prospective, randomized phase III US Intergroup trial comparing CHOP to 3 aggressive regimens, the standard CHOP regimen produced similar survival and was less toxic. This trial established CHOP as the standard of care for patients with DLBCL and other intermediate-grade NHLs.66 As mentioned above, based on phase II studies in which the empirical combination of rituximab in with CHOP had a good safety profile and induced response rates in more than 90% of patients with indolent and aggressive lymphoma, the Groupe d’Etude des Lymphomas de l’Adulte undertook a study to compare CHOP plus rituximab with CHOP alone in patients over the age of 60 years with DLBCL. With a median follow-up of 2 years, the OS was higher in the R-CHOP group,33 and this trial continued to demonstrate statistically significant benefits in event-free survival (EFS), PFS, and OS for R-CHOP with longer follow-up.37 These findings were confirmed in a US intergroup trial where the 3-year failure-free survival rate was 53% for R-CHOP patients and 46% for CHOP patients (P = .04).45 In addition, the MabThera international Trial (MInT) examined the benefits of rituximab with chemotherapy in younger patient with DLBCL. In the MInT 824 patients from 18 countries were randomly assigned to 6 cycles of a CHOP-like regimen and rituximab or to 6 cycles of CHOP-like chemotherapy alone. Patients assigned chemotherapy and rituximab had increased 3-year EFS and OS compared with those

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assigned chemotherapy alone.46 Additional trials have confirmed the benefits of adding rituximab to CHOP-like regimens67 establishing R-CHOP as the standard of initial therapy for patients with DLBCL. For several decades the treatment for all patients with CLL commonly involved monotherapy with alkylating agents such as chlorambucil. Single-agent therapy may still have some role in the management of older or unfit patients with CLL receiving palliative treatment because they are convenient to administer and often are well tolerated. Randomized clinical trials demonstrated that monotherapy with purine analogs improved ORR and CR rates compared with alkylating agents but found no statistically significant differences in OS.68 More recent randomized trials also have demonstrated significant improvements in PFS with bendamustine (21.6 months vs. and 8.3 months) and alemtuzumab (14.6 months vs. 11.7 months) when compared with chlorambucil.69,70 The current standard initial therapy for younger, fit patients with CLL is the combination of fludarabine, cyclophosphamide, and rituximab (FCR).68 In a single-institution phase II trial at the University of Texas MD Anderson Cancer Center, FCR achieved an ORR of 95% and a CR rate of 72%, and the 6-year OS and failurefree survival rates were 77% and 51%, respectively.71 Median time to progression (TTP) was 80 months. These promising results, prompted the German CLL Study Group to perform a phase III trial comparing FCR to fludarabine and cyclophosphamide (the previous standard of care based on a randomized trial). FCR had a higher ORR (95% vs. 88%) and CR rate (44% vs. 23%) and a longer median PFS (51.8 months vs. 32.8 months).38 These results recently led the Food and Drug Administration (FDA) to approve FCR for treatment-naive patients with CLL. Standard first-line therapy for HL has also been established based on randomized controlled clinical trials as discussed below.

Challenges Although standard approaches for initial therapy have been well defined by randomized controlled clinical trials for some lymphoid malignancies as demonstrated by the examples above, for other lymphomas, the optimal initial therapy remains less clear. For instance, anthracycline-based chemotherapy remains the standard treatment for patients with PTCL although such regimens have failed to induce sustained remissions for most patients. The most notable exception are patients with anaplastic lymphoma kinase positive anaplastic large cell lymphomas who have more favorable outcomes.72 The role of anthracyclines in the treatment of PTCL has recently been questioned. Notably, the International PTCL Clinical and Pathologic Review Project retrospectively demonstrated no difference in OS comparing patients who did or did not receive an anthracycline for PTCL (Figure 1).73 Previous studies have established worse outcome for PTCL compared with aggressive B-cell NHL treated with anthracycline-based chemotherapy, in terms of response, relapse, and OS rates.74-76 Though anthracycline-based therapy tends to produce reasonable CR rates (approximately 50%), 5-year OS remains poor for patients with most PTCL subtypes. Modifications to CHOP including increasing dose density or dose intensity,77 adding agents like gemcitabine and etoposide,47,78,79 denileukin diftitox,80 and alemtuzumab81 among others have been proposed but have yet to demonstrate ben-

Christopher R. Flowers, James O. Armitage efits over CHOP similar to those described above for DLBCL. At present, the most promising approach appears to be to start anew in designing specific regimens for PTCL patients based on biology. One possible candidate to include in such an approach is the antifolate agent, pralatrexate that produced a 28% OR rate in patients with relapsed/refractory PTCL and 49% rate of disease control leading to its FDA approval in this setting.82,83 However, building novel regimens for PTCL will be considerably challenging given the rarity of the disease, the heterogeneity, and number of PTCL subtypes, and the existing limitations of clinical and preclinical data for constructing rational combinations.

Reduced Toxicity for Hodgkin Lymphoma Before the 1960s, single-agent chemotherapy agents were used for the treatment of patients with HL and produced 5-year disease-free survival rates of < 10%. For patients with HL, combination chemotherapy has been established as the standard initial therapy since the 1970s when the combination of mechlorethamine, vincristine, procarbazine, and prednisone demonstrated an ORR of 80% and produces long-term disease-free survival in > 50% of patients.84 Following the development of MOPP a number of approaches have been explored to examining alternating hybrid chemotherapy regimens, reduced intensity induction, more intensive combination chemotherapy regimens, and alternative non-cross-resistant agents. Studies ultimately led to the establishment of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as the standard of care for HL. ABVD initially demonstrated a CR rate of 75% which was equivalent to MOPP, and had advantages because it was less leukemogenic, had much lower rates of sterility and premature menopause, and was partial non-cross resistant with MOPP.85 Early randomized trials showed that ABVD was superior to MOPP86-88 and equivalent to the MOPP/ABV hybrid which was substantially more toxic.89 As a result, ABVD has became the standard initial regimen in the United States. In other trials, ABVD was superior or equivalent to other more toxic aggressive, multiagent chemotherapy regimens.90-93 The treatment of HL has changed remarkably over the past several decades, making HL one of the most curable human cancers. At present, about 80% of patients achieve long-term disease-free survival. Modern front-line treatment approaches for HL are attempting to further improve outcome and reduce therapy-related complications, such as cardiovascular and pulmonary toxicity, infertility, and secondary malignancies. Ongoing trials for patients in early stages are investigating lower radiation doses, smaller radiation fields, and possible reductions in the doses or number of cycles of chemotherapy given. Following the demonstrated benefits of MOPP and ABVD for advanced-stage disease as noted above, management of localized HL shifted from approaches employing radiation alone to adding chemotherapy in early stage HL, in a large part because of the long-term toxicity and mortality related to large radiation fields. The management of early-stage HL continues to evolve.94

Challenges Although most patients with HL will be cured with current treatment strategies, approximately 10%-20% of patients, particularly

Table 3 Diffuse Large B-Cell Lymphoma Prognostic Groups Risk Group

Risk CR, % Factors, N

5-Year OS, %

Patients (All Ages) Low

0-1

87

73

Low Intermediate

2

67

51

High Intermediate

3

55

43

4-5

44

26

Low

0

92

83

Low Intermediate

1

78

69

High Intermediate

2

57

46

High

3

46

32

High Patients 60 Years of Age or Younger

Adverse risk factors correlated with response to chemotherapy and survival: (1) older than 60 years of age; (2) LDH > normal; (3) PS ≥ 2; (4) Ann Arbor stage III/IV; (5) extranodal involvement; (6) > 1 site (prognostic for patients older than 60 years of age only). International NHL Prognosis Factors Project.99 Abbreviations: CR = complete response; DLBCL = diffuse large B-cell lymphoma; LDH = lactate dehydrogenase; NHL = non-Hodgkin lymphoma; OS = overall survival; PS = performance status

those with advanced and symptomatic disease, do not respond to the first-line therapy. Among these patients, approximately 50% of individuals with primary refractory or relapsed HL can be successfully salvaged with intensified high-dose chemotherapy combined with autologous stem-cell transplantation.95 However, patients who fail to respond to autologous transplantation generally have very poor outcomes. Some efforts to avoid these adverse outcomes have focused on providing more intensive initial therapy, particularly for poor risk patients. In particular, the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) was introduced in 1990 by the German Hodgkin’s Lymphoma Study Group as a means to increase dose. Dose escalated BEACOPP demonstrated a significantly lower rate of primary progressive disease during initial therapy than COPP (cyclophosphamide/vincristine/procarbazine/ prednisone)/ABVD (2% vs. 12%; P < .001).96 The superiority of dose-escalated BEACOPP was most pronounced in patients with poor risk International Prognostic Score (IPS; 4-7). When compared with ABVD in another trial, BEACOPP also demonstrated statistically significant improvements in the CR rate (81% vs. 70%), 5-year failure-free survival (FFS; 78% vs. 65%), and 5-year PFS (81% vs. 68%), but not 5-year OS (92% vs. 84%).97 However, a randomized trial comparing outcomes following firstline chemotherapy, ABVD (n = 166) or BEACOPP (n = 155) with preplanned high-dose salvage for patients with primary refractory or relapsed HL showed that BEACOPP provided superior freedom from progression following first-line therapy (87% vs. 71%) but no differences in 3-year freedom from progression or 3-year OS following second-line therapy (92% vs. 87% and 90% vs. 91%, respectively).98 Other promising avenues for improving outcomes for relapsed HL patients include anti-CD30 antibodies alone (eg, MDX-060, SGN-30) or tied to an immunotoxin (eg, SGN-35), rituximab, galiximab, histone deacetylase inhibitors, and mammalian target of rapamycin inhibitors.95

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A Decade of Progress in Lymphoma Development of Prognostic Systems The International Prognostic Index (IPI) was initially described in 1993 and remains a principle means for predicting outcomes for patients with aggressive NHLs.99 The IPI score is calculated by giving 1 point for each of the 5 risk factors: stage III/IV disease, elevated lactate dehydrogenase (LDH), age > 60 years, Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of > 1 extranodal site. The IPI stratifies patients into distinct risk groups with a 5-year OS ranging from 26% to 73% (Table 3). However, the IPI was developed during the period before rituximab was routinely included in treatment regimens for DLBCL. In a population-based, retrospective cohort study of patients with newly diagnosed DLBCL treated within the British Columbia Cancer Agency with rituximab plus standard chemotherapy, a revised IPI grouping improved prediction of PFS over the original IPI categories.100 Patients with 0 risk factors had a 94% 4-year PFS, patients with 1-2 risk factors had 80% PFS, and those with ≥ 3 risk factors had 53% PFS (Table 3). Other studies have demonstrated improved outcomes for all IPI categories with R-chemotherapy regimens.37,46 At present, the IPI remains the primary prospectively designed and validated measure for assessing aggressive lymphoma prognosis, but additional prospective studies are needed to improve our ability to predict treatment outcome, particular when DLBCL patients are additional stratified by lymphoma subtype. An early predictive model specific to FL was proposed by the Intergruppo Italiano Linfomi (ILI) in 2000 using, gender, systemic symptoms, the number of extranodal sites of disease, ESR, and LDH.101 The ILI model segregated FL patients into 3 groups (low, intermediate, and high risk) with 5-year survival rates of 90%, 75%, and 38%; and 10-year survival of 65%, 54%, and 11%, respectively. In 2004, Solal-Céligny and colleagues proposed the Follicular Lymphoma International Prognostic Index (FLIPI) as a more discriminant model than the IPI for defining prognosis for FL.102 In the FLIPI model, 5 adverse prognostic factors were identified: age (> 60 years vs. < 60 years), Ann Arbor stage (III-IV vs. I-II), hemoglobin level (< 12 g/dL vs. > 12 /dL), number of nodal areas (> 4 vs. < 4), and serum LDH level (above normal vs. normal), and 3 risk groups were defined: low risk (0-1 adverse factor, 36% of patients), intermediate risk (2 factors, 37% of patients, hazard ratio [HR] of 2.3), and poor risk (> 3 adverse factors, 27% of patients, HR of 4.3). However, role of FLIPI in the modern era of R-chemotherapy as initial therapy is unclear. Recently, the FLIPI2 has been recently proposed using 5 covariates B2M > upper limit of normal (ULN), longest diameter of the largest involved node (LoDLIN) > 6 cm, BMI presence, Hb < 12 g/dL, and age > 60 years that were predictive.38 FLIPI2 demonstrated 3-year PFS of 78%, 68%, and 52% for patients in the low-risk, intermediate-risk, and high-risk groups, respectively (P < .00001). Similar systems for predicting treatment outcomes have been developed for other NHLs.103,104 For patients with advanced-stage HL, the IPS utilizes 7 risk factors (male gender, age ≥ 45 years, stage IV disease, albumin < 4 g/dL, a hemoglobin level < 10.5 g/dL, a leukocytosis count of at least 15,000/ mm3, and a lymphocyte count of < 600/mm3 or < 8% of the white cell count, or both) that predict the likelihood of freedom from disease progression.105 This study was devised using patients treated with che-

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motherapy with or without radiation. The 7 adverse prognostic factors had similar independent prognostic effects. Five-year freedom from progression rates based on the number of factors ranged from 84% for those with 0 factors to 42% for those with ≥ 5 factors.

Challenges However, the IPS does not include all potentially important adverse prognostic features on presentation. For example, other prognostic factors that may be important include B symptoms, disease bulk, histologic subtype, number of nodal sites of disease, number of organs involved, bone marrow involvement, erythrocyte sedimentation rate, platelet count, serum alkaline phosphatase, serum lactate dehydrogenase, and comorbidities.86,88,106-109 Fluorodeoxyglucose (FDG) positron emission tomography (PET) has emerged over the last decade as a functional imaging technique with distinct advantages over conventional nuclear scintigraphy. FDG-PET improves detection of disease sites above and below the diaphragm in the staging of lymphoma and persistently positive PET scans during and after chemotherapy have a high sensitivity for predicting subsequent relapse for some lymphomas. Because of these characteristics, PET scans rapidly replaced 67Ga imaging in the staging and evaluation of patients with lymphoma.110 In 2007, the revised International Working Group response criteria for malignant lymphoma recommended the use of PET for patients with routinely FDG-avid, potentially curable lymphomas before treatment to ascertain the extent of disease, at least 6 weeks following completion of therapy for assessment of CR, and in the context of a clinical trial mid-treatment to evaluate the prognostic ability of interval PET.111 With the increasing use of PET for the staging and restaging for lymphoma patients, early-response measured by PET has been identified as a potentially powerful prognostic tool in HL and NHL.112-115 In a study by Gallamini et al that included 260 patients with stage II-IVB Hodgkin lymphoma, the 2-year PFS rate for patients with positive versus negative PET results after 2 cycles of chemotherapy (PET-2) were 12.8% and 95.0%, respectively (P < .0001).115 As such, trials have been designed investigating the role of response-adapted therapy based on early PET findings.94 PET Scanning as a Prognostic Indicator in Lymphoma. Given its potential predictive power and its apparent independence from the treatment selected,116 interim fusion PET/CT imaging or other functional imaging modalities may become important clinical tools for DLBCL patients in the future. Nevertheless, even in HL where early interim PET is establishing its prognostic value, there are limited data to support a role for PET scanning in routine followup, and this practice is not recommended by current guidelines.117 More generally, there is not yet an established role for interim PET scans across most lymphoma subtypes during treatment or for surveillance PET for patients in CR. The majority of studies evaluating FDG-PET in lymphoma involve patients with HL or DLBCL, with fewer on the benefits PET as a prognostic tool in other lymphoma subtypes. Moreover, majority of studies are retrospective, unblinded, and compare PET with other imaging modalities rather than biopsies of the active lesions.110 Early restaging PET scans performed after 1 to 4 cycles of therapy have been shown to be predictive of outcome in some, but not all, studies.118-121

Christopher R. Flowers, James O. Armitage In particular, in a study of 98 patients with DLBCL treated with R-CHOP at the Memorial Sloan-Kettering Cancer Center who underwent risk-adapted therapy based on PET results after 4 cycles, 51 of 59 patients with a negative PET scan were progression free at a median follow-up of 44 months. However, 38 patients with a positive PET underwent repeat biopsy; 33 were negative, and 26 remain progression free after consolidation therapy.121 The timing of PET with respect to chemotherapy and radiation administration must also be carefully considered because treatment-related effects may lead to falsely positive results. Moreover, the additional risks of radiation exposure from PET or any other imaging modality should be consider in discussion of routine use for surveillance.122

Conclusion Our ability to manage patients with lymphoma has improved dramatically in the past decade, yet several challenges remain that must be overcome to continue advances in the decades to come. The advent of classification and prognostic systems for the lymphomas has markedly improved our ability to stratify patients into clinically meaningful populations and predict their likely outcomes with conventional therapies. Future efforts will require strategies that separate patients into biologic meaningful prognostic subgroups that will allow us to apply rationally-defined treatment regimens aimed at improving outcomes for poor-risk subsets and reducing toxicity for good-risk patients. Over the past decade, the survival of patients with the 2 most frequent B-cell lymphomas, DLBCL and FL, have improved significantly with the incorporation of rituximab into the standard treatment regimens. To continue improving outcomes in the years to come for DLBCL and HL, we will clearly need to separate poor-risk patients and develop specific regimens and trials for these populations, otherwise designing adequately powered randomized, controlled trials for DLBCL and HL will be challenging when the response and survival rates for these diseases as a whole are so favorable. New insights into the biology of lymphomas and the mechanisms of response and relapse following lymphoma therapies will aid us in the design of these trials in the decades to come.

Disclosures James O. Armitage has served as a paid consultant or has been on the Advisory Board of Allos Therapeutics, Inc.; Seattle Genetics, Inc.; and Ziopharm Oncology, Inc. Christopher R. Flowers has received research support from Millennium Pharmaceuticals, Inc./Takeda Pharmaceutical Company Limited; Spectrum Pharmaceuticals, Inc.; and Wyeth Pharmaceuticals; and has also served as a paid consultant or has been on the Advisory Board of Biogen Idec; Celgene Corporation; Genentech, Inc.; Intellikine; and Roche Pharmaceuticals.

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