Treatment of Non-Hodgkin's Lymphoma: A Look over the Past Decade

Treatment of Non-Hodgkin’s Lymphoma: A Look over the Past Decade Bertrand Coiffier

Abstract The past decade has seen enormous changes in our understanding of lymphomas with a better classification (World Heath Organization) and identification of better prognostic factors; however, important genetic prognostic factors have not been completely analyzed. The appearance of rituximab and other monoclonal antibodies has completely revolutionized the treatment of this disease. If monoclonal antibodies have activity when used alone, most patients experienced relapse after such a treatment, even after maintenance therapy. The combination of rituximab with chemotherapy has now been shown in several randomized studies to increase the response rate, decrease the relapse rate, and prolong progression-free survival and overall survival. Rituximab plus CHOP (cyclophosphamide/doxorubicin/prednisone/vincristine; R-CHOP) has become the standard for patients with diffuse large B-cell lymphoma. Rituximab chemotherapy, probably with the CHOP regimen, is slowly gaining importance as the standard for patients with follicular lymphoma. Although little is known for other indolent lymphomas and mantle cell lymphoma, progress has been made there, too. Several questions remain for future randomized studies to continue our search toward cure.

Clinical Lymphoma & Myeloma, Vol. 7, Suppl. 1, S7-S13, 2006 Key words: Diffuse large B-cell lymphoma, Follicular lymphoma, Mantle cell lymphoma, Monoclonal antibodies, Peripheral T-cell lymphoma

Introduction Non-Hodgkin’s lymphomas (NHLs) have seen a lot of improvements during the past decade: new classification with new entities, new prognostic parameters and indexes, and new therapeutic modalities, particularly the use of monoclonal antibodies (MoAbs). This has resulted in a complete change of our understanding of lymphoma, allowing different strategies for improving the treatment of patients.

Lymphoma Subtypes and Classifications In the beginning of the past decade, patients with lymphoma were mainly classified according to the Working Formulation for Clinical Usage described in 1982 under the auspices of the National Cancer Institute,1 even if some European pathologists preferred to use the Kiel Classification.2 With the appearance of new immunologic, cytogenetic, and genetic tools, new lymphoma subtypes were recognized, like mantle cell lymphoma or marginal zone lymphoma of the mucosa-associated lymphoid tissue.3,4 As a result, European and American pathologists proposed a new classification, the Revised European-American Lymphoma classification that matured into the World Health Organization classification that is currently used.5,6 Even if some subtypes were clearly not definitive, like peripheral T-cell lymphoma, this Université Claude Bernard, Lyon, France Submitted: Apr 19, 2006; Revised: Jun 6, 2006; Accepted: Jun 19, 2006 Address for correspondence: Bertrand Coiffier, MD, Hematology Department, CH Lyon-Sud, 69495 Pierre Benite, France Fax: 33-478-86-4354; e-mail: [email protected]

classification is always in use and will probably stay for some more years (Table 1).6 Currently, the analysis of genetic abnormalities with newly developed tools like complementary DNA microarray technology or chromosomal comparative genomic hybridization allows the recognition of new subtypes, a better definition of current subtypes, and definition of new prognostic parameters.7-9 However, these analyses are currently ongoing and, even if they had succeeded in individualizing new entities with different outcomes, they have not yet led to change of therapeutic strategies.10

Prognostic Parameters and Indexes The search for prognostic tools has been part of the story of any cancer treatment, particularly in cancers in which curative strategies exist. More than 30 years ago, prognostic parameters such as lactate dehydrogenase, `2-microglobulin, or Ann Arbor staging system were described.11-13 The appearance of prognostic indexes came later in the 1980s.14 All the described prognostic indexes were related to a specific chemotherapy regimen but included nearly the same parameters, so several investigators decided to work together, and finally, the International Prognostic Index (IPI) was described in 1993 (Table 2).15 Even if this index only uses surrogate markers, they are so powerful that this index is always in use for choosing the treatment of any patients. The IPI was initially described for patients with aggressive lymphomas but was secondarily applied to other lymphoma subtypes and was shown to have the same ability to pinpoint patients with high-risk disease.16,17 An analysis of a large group of patients with follicular lymphoma (FL)

Dr. Coiffier has received research support from Roche and Genentech BioOncology and has served as a paid consultant for Roche, Genentech BioOncology, Johnson & Johnson, and sanofiaventis. He is also a member of the Speaker’s Bureau for Roche, Genentech BioOncology Millennium, Johnson & Johnson, and sanofi-aventis. This article includes discussion of investigational and/or unlabeled uses of drugs, including the use of Yttrium 90 ibritumomab tiuxetan, Iodine 131 tositumomab, hA20, ofatumumab, ocrelizumab, epratuzumab, apolizumab, and galiximab alone or in combination with chemotherapy in the treatment of non-Hodgkin’s lymphoma.

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Treatment of Non-Hodgkin’s Lymphoma Table 1 World Health Organization Classification of Lymphomas6 B-Cell Neoplasms Lymphoma/leukemia Precursor B-lymphoblastic leukemia/lymphoma Small lymphocytic lymphoma B-cell prolymphocytic leukemia Hairy cell leukemia Lymphoplasmocytoid lymphoma or immunocytoma

Table 2 International Prognostic Index15 International Prognostic Index (Score, 0-5)

Age-Adjusted International Prognostic Index (Score, 0-3)

Age (< 60 years or • 60 years) Performance status (0-1 or > 1) Stage (localized or disseminated) Number of extranodal sites (0-1 or > 1) LDH level (normal or increased)

Performance status (0-1 or > 1) Stage (localized or disseminated) LDH level (normal or increased)

Low-risk group: score, 0 or 1 Low-intermediate–risk group: score, 2 High-intermediate–risk group: score, 3 High-risk group: score, 4 or 5

Low-risk group: score, 0 Low-intermediate–risk group: score, 1 High-intermediate–risk group: score, 2 High-risk group: score, 3

Indolent nodal or extranodal lymphomas Marginal zone B-cell lymphoma MALT-type lymphomas Splenic marginal zone lymphoma Nodal lymphomas Follicular lymphomas Mantle cell lymphoma Aggressive nodal or extranodal lymphomas Diffuse large B-cell lymphoma Burkitt’s lymphoma/leukemia T-Cell Neoplasms Lymphoma/leukemia Precursor T-lymphoblastic lymphoma/leukemia Prolymphocytic leukemia Large granular lymphocyte leukemia Natural killer cell leukemia Mycosis fungoides/Sézary syndrome Nodal or extranodal lymphomas T-cell, natural killer cell, or ab T-cell lymphomas Subcutaneous panniculitic T-cell lymphoma Intestinal (enteropathy-associated) T-cell lymphoma ab T-cell hepatosplenic lymphomas Peripheral T-cell lymphomas Anaplastic large-cell lymphoma CD30+ T-cell cutaneous lymphoproliferative syndromes Lymphoma/leukemia secondary to HTLV-1 infection Hodgkin’s Lymphoma Predominantly lymphocytic nodular Hodgkin’s lymphoma Classic Hodgkin’s Hodgkin’s-like anaplastic large-cell lymphoma Abbreviation: MALT = mucosa-associated lymphoid tissue

allowed the description of an index specific to these patients, the Follicular Lymphoma IPI, and retained parameters not so different from the ones composing the IPI18: age (* 60 years), stage (disseminated), hemoglobin level (< 12 g/dL), lactate dehydrogenase level (increased), and number of nodal sites (> 4). Hemoglobin level was not evaluated in the IPI study but has always been associated with outcome.19

The score is calculated given 1 for the presence of 1 of the parameters dividing patients into 6 groups, 0-5. Because of similar survival curves, some groups have been added, making only 4 prognostic subgroups. The age-adjusted IPI was described for patients aged < 60 years to eliminate age that is not really related to the tumor. Abbreviation: LDH = lactate dehydrogenase

Currently, new prognostic parameters are evaluated, particularly biologic markers related to tumor proliferation or pathways linked to apoptosis.20-22 Among them, the expression of Bcl-2 protein, probably related to refractoriness to standard chemotherapy drugs, persists as one of the most important parameters.23 Recently, it has been shown that the expression of Bcl-2 protein or interleukin-6 protein, a marker of germinal center B-cell diffuse large Bcell lymphoma (DLBCL), might influence the response to the rituximab plus CHOP (cyclophosphamide/doxorubicin/prednisone/vincristine; R-CHOP) regimen.24,25 The objective of the future studies will be to individualize the most important parameters among all these genes and proteins and describe an index for all lymphomas or for specific subtypes like DLBCL. First, we have to standardize these parameters. For a long time, patients with initial bulky tumor and persistent images on the computed tomography scan at the end of therapy were considered at risk for relapse even if few of them experienced relapse, hence the unconfirmed complete response (CR) status for evaluating the response.26 Recently, positron emission tomography (PET) scanning was introduced, and the uptake of [18F]fluorodeoxyglucose helps recognize metabolically active cells, particularly, but not only, lymphoma cells. Several studies have shown that patients with DLBCL with uptake on a PET scan at the end of therapy have a very low relapse rate.27 Contrarily, patients with a high uptake are at risk of relapse. By the same token, not all patients with positive PETs experience relapse because of false-positive fixation, particularly from macrophages, so such patients with a single spot need to have a histologic confirmation of lymphoma before intensifying the treatment. Patients with persisting uptake of [18F]fluorodeoxyglucose after a few cycles of chemotherapy (* 2) have been considered poor responders with high risk of failure.28 The question is, which treatment should be given to these patients? Because those who currently receive MoAb or autologous transplantation have not succeeded in inducing a good response.

Therapeutic Modalities The past decade has seen the appearance of MoAbs in the treatment of B-cell lymphoma, whereas very little progress for T-cell lymphoma was made. Rituximab, an anti-CD20 chimeric antibody, was the first MoAb tested and showed evidence of benefit for patients in randomized studies. Other MoAbs have demonstrated activity, but evidence of their input is lacking. Although MoAbs have activity when used alone, most of the benefit for survival is reached when rituximab is combined with chemotherapy.29-31

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Bertrand Coiffier Table 3 Results of Different Randomized Studies Comparing Chemotherapy with Rituximab plus Chemotherapy in Previously Untreated Patients31,36-44 Study/Treatment

Setting

CR Rate (%)

Median EFS

Median PFS

Median DFS

Median OS

DLBCL 60-80 Years All IPI Intent-to-treat analysis

75† 63

3.8 Years‡ 1.1 Years

Not reached‡ 1.5 Years

Not reached‡ 2.45

Not reached† 3.1 Years

DLBCL Age > 60 years Not published

Not available

Not available

At 3.5 years: 53%* 46%

Not available

NS

Not available

NS

GELA31,36 R-CHOP CHOP Intergroup37 R-CHOP CHOP R-CHOP plus Maintenance R-CHOP CHOP plus Maintenance CHOP

–

–

Not available

At 2 years: 79%‡ 77% 74% 45%

DLBCL Age < 60 years IPI score 0-1 Intent-to-treat analysis

86‡ 68

At 3 years: 79%‡ 59%

At 3 years: 85%‡ 68%

Not available

At 3 years: 93%‡ 84%

DLBCL Age 61-80 years All IPI Not published

Not available

Not available

At 2 years: P < 0.001

Not available

NS

FL All ages Need to be treated Intent-to-treat analysis

41‡ 11

Not available

27‡ 7

Not reached‡ 21

NS

FL All ages Need to be treated

20 17

Not available

Not reached‡ 2.5 Years

Not reached‡ Not reached

Not reached* Not reached

FL All ages Need to be treated Not published

76‡ 49

At 2.5 years: 78%† 62%

Not available

Not available

Not available

Indolent lymphomas All ages Need to be treated Not published

42‡ 20

Not reached‡ 19 Months

Not available

Not available

Not available

Indolent lymphomas All ages Need to be treated Not published

Not available

Not available

At 4 years: 58%* 34%

Not available

NS

MInT38 R-Chemotherapy Chemotherapy RICOVER39 R-CHOP-14 CHOP-14 CVP40 R-CVP CVP GLSG41 R-CHOP CHOP (Second Randomization Without Published Results) FL-200042 R-CHVP-Interferon CHVP-Interferon OSHO43 R-MCP MCP ECOG44 CVP then Rituximab CVP

Abbreviations: ECOG = Eastern Cooperative Oncology Group; GELA = Groupe d’Etude des Lymphomes de l’Adulte; GLSG = German Low-Grade Lymphoma Study Group; MCP = mitoxantrone/chlorambucil/prednisolone; NS = not significantly different; OSHO = Eastern German Study Group for Haematology and Oncology *P < 0.05. †P < 0.01. ‡P < 0.001.

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Treatment of Non-Hodgkin’s Lymphoma Diffuse Large B-Cell Lymphoma In the early 1990s, different chemotherapy regimens studied in phase II trials showed superiority over the CHOP regimen. Fisher et al clearly demonstrated that this issue was related to a bias in the selection of patients in these trials and that the CHOP regimen was associated with similar results regarding time to progression or overall survival (OS) than more complicated regimens and was less toxic than the complicated regimens.32 After these results, studies intensifying the treatment with high-dose therapy and autologous transplantation have shown that this treatment might benefit a subgroup of young patients with lymphoma, but they did not increase the response rate in older patients.30,33 Other studies used more dose-intense or dose-dense regimens and also showed some benefit over the standard CHOP regimen.30,34,35 After demonstration of rituximab activity in DLBCL and satisfactory toxicity profile when combined with the CHOP regimen, 2 phase III studies of the R-CHOP regimen were launched for elderly patients.36,37 The first one, run by the Groupe d’Etude des Lymphomes de l’Adulte, was recently updated with a 5-year median follow-up, and the second is not yet published (Table 3).31,36-44 This study included elderly patients with DLBCL not previously treated, 60% of them having a high-risk IPI score. Rituximab combined with CHOP significantly increased the CR rate; decreased the progression rate during or after treatment and the relapse rate; improved duration of event-free survival (EFS), progression-free survival (PFS), diseasefree survival (DFS), and OS.31,36 These results were observed in patients with low- or high-risk IPI score. Three other studies have confirmed the benefit associated with the combination of rituximab plus CHOP or CHOP-like regimens (Table 3).37-39 The US Intergroup study randomized elderly patients to receive CHOP or R-CHOP, but rituximab was only given once every 2 cycles of CHOP, and it secondarily randomized responders between rituximab maintenance for 2 years versus no maintenance.37 Because of this second randomization, global results are difficult to analyze. Rituximab combined with CHOP significantly prolonged PFS but not OS when all randomized patients were analyzed, and rituximab maintenance significantly decreased progression after treatment (Table 3). The results of the second randomization lacks follow-up to be completely analyzed but showed that rituximab maintenance did not have an additive effect if the patients initially received R-CHOP. The MInT (MabThera International Trial) study included young patients with good-risk DLBCL treated with CHOP or CHOP-like regimens with or without rituximab.38 With a median follow-up of nearly 3 years, EFS, PFS, and OS were significantly superior for patients treated with rituximab. The RICOVER study compared R-CHOP-14 with CHOP-14 and confirmed improved outcome when rituximab is combined with CHOP.39 The superiority of R-CHOP-14 compared with RCHOP-21 was not investigated in this study. Very little data exist for other MoAbs in the setting of DLBCL. A phase II study with yttrium 90 ibritumomab tiuxetan showed activity at time of relapse in rituximab-free patients but not in patients experiencing progression after a rituximab-containing regimen.45 The combination of rituximab plus CHOP for patients with DLBCL is now considered the gold-standard first-line treatment. Whether other chemotherapy regimens will do better than R-CHOP-21 is not known and is certainly the most important question, because the improvement in survival for some subgroups is not satisfactory. Several studies are currently comparing different regimens. In the MInT study, the benefit of the addition of

etoposide to CHOP disappeared when rituximab was combined with CHOP or CHOEP (CHOP plus etoposide).38 Does that mean that the benefit of dose-dense or dose-intense regimens compared with CHOP will be less or nonexistent when rituximab is combined with CHOP, ie, the same therapeutic results will be reached with fewer adverse events? Will high-dose therapy with autologous transplantation stay a valid option for young patients with high-risk DLBCL in CR? Prospective studies targeting these important questions and analysis of different mechanisms of action of rituximab, particularly antibody-dependent cellular cytotoxicity in patients treated with chemotherapy, are warranted.

Peripheral T-Cell Lymphoma Because of the diversity and the rarity of these lymphomas, the current classification is always evolving. We do not know how to treat them or reach long remissions in a significant group of patients. Few prospective studies have addressed these lymphomas, and our knowledge rests only on phase II studies with fewer patients.46 Even high-dose therapy with autologous transplantation has not demonstrated its benefit.47 The better understanding of genetic abnormalities in these different lymphomas might allow us to define potential active treatment options in the future.48 Currently, the only option we have is to treat them as DLBCLs without rituximab, which is not satisfactory. However, nothing new better than the CHOP regimen is available. Even high-dose therapy with autologous transplantation did not seem to have the same benefit than in DLBCL.49

Follicular Lymphoma At the beginning of the past decade, FL was considered an incurable disease. Some groups preferred light chemotherapy regimens (CVP [cyclophosphamide/vincristine/prednisone]) even if it meant retreatment every 12 months or 18 months, and others preferred more intense chemotherapy with doxorubicin and/or interferon to reach a better response.50 Rituximab was first tested in patients with FL experiencing relapse and has rapidly shown its activity.51 However, rituximab alone has a short response duration, and rituximab maintenance was needed to have a long PFS.29 However, even patients treated with rituximab maintenance in the first-line setting experienced relapse. As in DLBCL, studies combining rituximab and chemotherapy for FL were launched (Table 3). Marcus et al compared R-CVP (rituximab plus CVP) with CVP alone in patients with FL: R-CVP was superior to CVP alone in terms of CR rate, response rate, EFS, PFS, DFS, and time to next treatment but was not superior for OS.40 This lack of superiority with a short follow-up might be secondary to the fact that patients experiencing progression received rituximab alone or in combination with chemotherapy. Three other studies have shown the same benefit with the addition of rituximab to chemotherapy (Table 3).41-43 If the patients included in these 4 studies have nearly similar characteristics, the chemotherapy regimens differ and allow us to have some insight into the therapeutic role of different drugs. The German LowGrade Lymphoma Study Group study is difficult to analyze because of the second randomization in responding patients between high-dose therapy with autologous transplantation and interferon in young patients and interferon doses in elderly patients. These 2 studies, incorporating doxorubicin and interferon, CHOP, or CHVP (cyclophosphamide/doxorubicin/vindesine/prednisone) regimens, seem to have superior results than those published with

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Bertrand Coiffier CVP with or without rituximab. The PFS with CHVP-interferon is similar to R-CVP, and PFS with R-CHVP-interferon is quite superior to that seen with R-CVP. Hochster et al studied rituximab maintenance in patients with FL responding to the CVP regimen (Table 3).44 Patients receiving rituximab maintenance had a longer DFS, but in the results presented earlier, there was no plateau, and DFS seems inferior to the concurrent combination of CHOP/CHVP and rituximab. However, rituximab maintenance was proven to add activity in the setting of patients with relapsing disease and must be tested after rituximab chemotherapy in untreated patients.52 These results confirm that for FL, the combination of chemotherapy plus rituximab improved response to treatment and PFS, and this might translate into a longer survival, so at least the combination of rituximab with chemotherapy seems to be a standard therapy for patients with FL. It is not yet demonstrated which regimen is better, but the comparison of CR rates, EFS, and PFS from different studies seems to show a larger benefit with the R-CHOP/R-CHVP regimens. The comparison of results obtained with R-CHOP or R-CHVP with those reached with rituximab alone in the same type of patient population favors the combination of rituximab and chemotherapy. However, this conclusion needs to be taken with caution, because no randomized study has yet compared these different regimens, and data for OS are not yet known for all studies. Patients with localized disease are usually treated with localized radiation therapy, but more than half of them experience relapse.29 Advani et al showed that these patients initially might not be treated with treatment done at disease progression without detrimental effects.53 For patients with disseminated disease but absence of adverse prognostic parameters, the watch and wait strategy is always recommended.29 However, the good results obtained with rituximab and chemotherapy might change this concept in the future, particularly if R-CHOP prolongs survival.

Other Monoclonal Antibodies in Follicular Lymphoma Two MoAbs have been combined with a radionuclide therapy and have been registered for the treatment of patients with relapsing/refractory FL, yttrium 90– and iodine 131–labeled anti-CD20 antibodies (ibritumomab tiuxetan and tositumomab). Radiation immunotherapy with both drugs was associated with a high response rate in relapsing/refractory disease.54 Ibritumomab tiuxetan was not tested in untreated patients with FL. In this setting, tositumomab was associated with a long DFS time and high OR rate, but as in phase II trials, there was a bias in patient selection precluding any conclusion on the benefit of this treatment.55 Tositumomab after CHOP chemotherapy in previously untreated patients was investigated by the Southwest Oncology Group.56 In this group of 90 patients, the OR rate to CHOP/tositumomab was 90% with a CR rate of 67%. Of patients not in CR after CHOP, 57% improved their response after tositumomab. Estimated 2-year PFS was 81%. Southwest Oncology Group is currently conducting a study comparing tositumomab and rituximab in patients with FL treated with CHOP as first-line treatment. Only such a study can evaluate the benefit and toxicity of tositumomab in comparison with rituximab in first-line therapy of patients. Several MoAbs directed against CD20 (hA20, HuMax-CD20, ocrelizumab) or other antigens (epratuzumab for CD22, apolizumab for HLA-DRB chain, and galiximab for CD80) are currently

being tested in phase I/II studies. No definitive conclusion can be made regarding their activity, toxicity, and benefit compared with rituximab in first-line therapy of patients. The real interest of these new antibodies will have to be demonstrated in randomized studies and by comparison with rituximab.

Mantle Cell Lymphoma This lymphoma has an indolent onset and is refractory to chemotherapy, with a median PFS of 18 months and a median OS of 3 years. It is a B-cell lymphoma, and rituximab has proven efficacy, but even R-CHOP did not seem to prolong survival.57 Whether CHOP or an aracytine-containing regimen (hyperCVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone] or DHAP [cisplatin/cytarabine/dexamethasone] regimen) is the best regimen to combine with rituximab is not known. When all strategies that have shown some benefit are combined, ie, rituximab-chemotherapy followed by high-dose therapy and autotransplantation, then by rituximab maintenance, PFS, DFS, and OS times are prolonged in comparison with historical controls, but no plateau is observed.58 The understanding of biologic mechanisms related to the refractoriness to chemotherapy drugs might allow the development of new therapeutic agents.59 New drugs like bortezomib or temsirolimus have been associated with response in patients with relapsing disease but have not yet been incorporated in multidrug regimens for untreated patients.

Other Indolent Lymphomas Small lymphocytic lymphoma and lymphoplasmacytoid lymphoma are considered a small group and have rarely been studied alone. However, they represent approximately 8% of all patients with lymphoma and represent several subentities: the nodal form of chronic lymphocytic leukemia and splenic marginal zone lymphoma. No standard treatment is defined for these patients, but fludarabine-containing regimens combined with rituximab seem to have improved the outcome, at least in phase II studies and in comparison with historical patients treated with R-CHOP.60 These lymphomas need further investigation to define the subentities, genetic abnormalities, and therapy. Marginal zone lymphomas of the mucosa-associated lymphoid tissues have been shown to be initiated by chronic infections or chronic immunologic reactions.61 Antibiotic therapies eliminating the pathogen induce a response in 60% of cases. For those without a clear pathogen relationship or for those not responding to antibiotics, single-agent chemotherapy or rituximab yielded a good response.62 The outcome of nodal marginal zone lymphoma, which often transforms into aggressive lymphoma, is not good.63 No specific treatment has been proposed for this rare lymphoma. Splenic marginal zone lymphoma is now clearly individualized as a very indolent lymphoma manifested by splenomegaly and blood and bone marrow infiltration.64 Watch and wait followed by splenectomy at time of cytopenia or painful spleen is the best strategy to treat these patients. Chemotherapy may be delayed for 8-10 years after diagnosis in most of the cases.65 If in all these indolent lymphomas, rituximab and other MoAbs have activity, lack of prospective series precludes the definition of any standard treatment. Only large cooperative group studies including all of these lymphomas will allow us to clearly define their incidence and outcome and to propose specific treatment strategies.

Conclusion The past 10 years have certainly seen a lot of progress in lymphomas, particularly regarding pathology, prognostic, and

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Treatment of Non-Hodgkin’s Lymphoma therapeutic aspects. The appearance of MoAbs, particularly rituximab, has completely modified therapeutic options in B-cell lymphomas. If a cure is the objective of initial treatment for some patients, more progress is needed. If phase II studies are important for defining the use and toxicity of new drugs, major improvement might only be described with randomized studies.

26. 27. 28.

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