Management of Lymphoproliferative Disorders
The heterogeneous group of malignant diseases that fall within the heading of non-Hodgkin's lymphoma (NHL) are marked by the proliferation of a single, genetically identical clone of lymphoid cells in the lymph nodes, marrow, spleen, liver, gastrointestinal tract, nervous system, and other sites within the body. All types of NHL differ from Hodgkin's disease in lacking the Reed-Sternberg cells that are characteristic of the latter disease. Although NHL can be localized to a specific site, such as one or more lymph nodes, it is most often disseminated by the time it is first recognized.1,2
The diseases falling within the rubric of NHL also differ in their degree of virulence or aggressiveness, with some remaining in an inactive or indolent state for periods lasting as long as many years before they are detected or become aggressive, and others being rapidly virulent and aggressive, with varying outcomes.1,3 The various types of NHL are also classified according to the type of cell affected, whether B-lymphocytes, Tlymphocytes, or other types of cells; as well as by the size of the affected cells; and by the histologic appearance of the disease, whether nodular, in which the malignant cells exist in clusters or nodules among surrounding normal cells, or diffuse, in which the malignant cells have destroyed the normal structure of the lymph node, or some other appearance. While its causes remain unknown, NHL is also typified by cytogenetic abnormalities and the overexpression of various oncogenes.3
It is estimated that 56 390 new cases of NHL will occur in 2006, with 19 200 deaths from the disease.4 The incidence of NHL grows with increasing age, reaching about 8% to 10% per year among older patients.5
Of the various types of NHL, the disease that has shown the most significant increase in older persons is diffuse large B-cell lymphoma (DLBCL).5 More than 90% of patients with this condition, which is also the most frequently diagnosed NHL, are older than 60 years of age.6
Such aggressive types of NHL require intensive treatment, and in older patients, the achievement of complete remission of disease is the major determinant of outcome. Yet this has been difficult to accomplish in this age group because of toxicity and age-related factors, and efforts at reductions in the dosage and intensity of therapy have reduced its efficacy.5
Rituximab With Chemotherapy in the
Treatment of Diffuse Large-cell Lymphoma.
Historically, the regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, developed more than 30 years ago at the Children's Hospital of Philadelphia for which it is named–CHOP, has remained the "gold standard" of chemotherapy for DLBCL for more than a quarter century,6,7 despite the advent and examination of newer regimens.8 But while high-risk patients with NHL have shown greater survival when treated with dose-intense regimens of chemotherapy resembling CHOP, so called because they entail a greater frequency of dosing, these regimens, like others, often produce substantial toxicity in older persons.9 Moreover, many older patients' age or concurrent illnesses make them ineligible for the transplantation of stored autologous bone-marrow stem cells, which is the treatment of choice for relapsed DLBCL that continues to respond to treatment.6
The humanized monoclonal antibody rituximab targets and binds to the cell-surface antigen designated CD20, which is present on normal as well as malignant B-cells. Presence of the bound antibody on the B-cell surface induces antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity of the affected cells, including large numbers of the malignant B-cells present in DLBCL and other B-cell forms of NHL. Rituximab has been shown to act alone and synergistically with the CHOP regimen in several types of NHL, and was proved active against DLBCL in phase 2 clinical studies,6 in which it has produced response rates in the range of 30%.10
Recently, the 2 treatment strategies of adding rituximab to the CHOP regimen (RCHOP) and increasing the dose density by reducing the time between cycles of its use have been reported to improve outcomes in aggressive lymphomas.5 At the median 5-year follow-up of a French study begun in 2002, in which the R-CHOP regimen was compared with CHOP in 399 patients ranging in age from 60 to 80 years who had previously untreated DLBCL, 20% of those in the R-CHOP arm had experienced relapses of their disease, as compared with 34% in the CHOP arm. The median period of event-free survival after treatment was 3.8 years in the R-CHOP arm of the study versus 1.1 years in the CHOP arm. Over the 5-year course of follow-up, 47% of patients in the R-CHOP arm had been free of disease-related events, as opposed to 29% of those treated with the CHOP regimen. The 5-year overall survival in the 2 respective groups was 58% versus 45%.6 Moreover, at the time of the 5-year follow-up to the study, the median duration of survival without disease progression had still not been reached in the R-CHOP group of patients, whereas it had already been established as being 1 year for those treated with the CHOP regimen, and 66% of patients in the R-CHOP-treated group remained disease-free at 5 years, versus 45% in the CHOP-treated group.6
As a further component of this study, a percentage of patients in both the R-CHOP and CHOP arms who experienced relapses were retreated with regimens that differed according to the institution at which the retreatment was given. An examination of the data for patients found that those whose retreatment regimens included rituximab had a 58% rate of survival at 2 years after retreatment, as opposed to a 24% rate for those retreated without rituximab, and that patients treated with CHOP in the original study who were retreated with a rituximab-containing regimen after relapse survived for a significantly longer period than those who did not receive rituximab after relapse.6
In this French study, the addition of rituximab did not increase the incidence of toxicity with the CHOP regimen, although all R-CHOP-treated patients did show a greater likelihood of infection after the conclusion of treatment than did those in the CHOP-only group.6
The clinicians who conducted the French study concluded that its results support the idea that rituximab can increase overall survival when added to chemotherapy regimens for DLBCL, but that further study is needed. In addition, research is needed to develop maintenance therapy that can reduce older patients'relapse rate in DLBCL without increasing the toxicity of treatment.11
Over the past 3 years, various other trials have also reported better outcomes with the addition of rituximab to CHOP or CHOP-like regimens for treating DLBCL in both young and older patients.6 In an Italian study conducted from June 2002 to June 2004, 26 patients with stage III/IV DLBCL, ranging in age from 60 to 76 years, were treated with a regimen of rituximab followed on the next day by cyclophosphamide, doxorubicin, and vincristine, accompanied by prednisone given for 5 days. All of the patients were also given granulocyte colony-stimulating factor (G-CSF) on days 7 to 11 of each treatment cycle to minimize treatment-induced reductions in neutrophil counts and the accompanying risk of infection. The regimen was repeated every 2 weeks for a total of 6 full cycles. The intensity of this R-CHOP regimen, on the basis of its dose sizes and frequency of repetition at 2-week intervals, was twice that originally reported for the regimen in 1984, when it was used in treating metastatic breast cancer.12 As part of this study, patients whose DLBCL had spread beyond the lymph nodes and those with large or "bulky" sites of local disease were referred for radiotherapy whenever this was feasible.5
Of the 26 patients in the study, 24 received all 6 planned cycles of treatment with the intensified R-CHOP regimen.5 Twenty of the 26 patients in the study, or 77%, achieved complete remissions and 6, or 23%, achieved partial remissions, for an overall response rate of 100%.5 At a mean follow-up of 23 months, 79% of the patients were still alive.5 Despite the increase in treatment intensity from the original CHOP protocol, only 1 patient in the study died, as the result of a stroke, and although a significant reduction in the cardiac left-ventricular ejection fraction was among the potentially serious toxic effects of the intensified regimen, only 1 patient developed clinically evident heart failure, which was successfully managed medically. Severe, grade 3/4 adverse hematologic effects of the treatment regimen, in the form of neutropenia or anemia, occurred in 6 patients, while 3 others developed severe infections or diarrhea, and all of the patients in the study had alopecia or hair loss.5
While pointing to the need for a large multicenter trial to more fully determine the effects of dose-intensive R-CHOP therapy for DLBCL5, the clinicians who conducted the study, citing the very poor prognosis of the study patients at the time of their diagnosis, concluded that the results of treatment with the intensified R-CHOP regimen were "very encouraging"5 and confirmed the safety and efficacy of a dose-dense regimen of CHOP for treating older patients with aggressive, high-risk NHLs such as DLBCL. They further pointed out that the addition of rituximab can increase the rate of response to such a regimen without increasing its toxicity.5
In addition to its benefit in DLBCL, rituximab has shown potentially important effects in the combination chemotherapy of mantle-cell lymphoma (MCL), another type of NHL.6 Besides occurring in diffuse and nodular patterns, which are aggressive, fail to respond well to conventional chemotherapy with regimens containing the drug doxorubicin, and have a poor prognosis, MCL also occurs in the variant known as mantlezone MCL, which behaves clinically in a manner similar to that of indolent forms of NHL.13 In MCL, as in DLBCL, response rates to rituximab are in the range of 30%.10
The addition of rituximab to the CHOP regimen has produced responses in 98% of patients treated with it for MCL, and complete responses in 48%, although the median duration of response has been only 16 months.13
Comparably effective has been alternating treatment with regimens involving the cytotoxic drugs cyclophosphamide, vincristine, doxorubicin, and the steroid drug dexamethasone (hyper-CVAD) and high doses of the drugs methotrexate and cytarabine, which has produced responses in up to 93.5% of patients with aggressive variants of MCL.13
This positive result with the hyper-CVAD regimen in alternation with methotrexate and cytarabine prompted a study in which rituximab was added to both of these regimens, given in 4 cycles to 100 patients with newly diagnosed aggressive MCL, of whom 96 had stage IV disease. In this study, the antiviral drug valacyclovir, the antifungal drug fluconazole, and the antibacterial antibiotic levofloxacin were also given after each infusion of doxorubicin, as means for preventing infection, and G-CSF was given to promote granulocyte replacement during chemotherapy as another measure for reducing the risk of infection. In the study, patients who exhibited a complete response after 2 cycles of the rituximab-plus-hyper-CVAD regimen and one cycle of rituximab/methotrexate/cytarabine were given 4 more cycles of treatment, for a total of 6 cycles, while those showing a complete response after 6 cycles received 2 more cycles, and those with disease remaining after 6 cycles had their treatment stopped.13
Of 97 patients whose responses to treatment could be assessed, 97% responded to the 2-part treatment regimen and 87% had a validated or unconfirmed complete response. At a median follow-up of 40 months, survival without relapse was 64% for the evaluable study group and 74% for its members aged 65 or younger, while overall survival was 82%.13 Hematologic toxicity was the major adverse effect of treatment, in the form of neutropenia and thrombocytopenia. Five treatment-related deaths occurred during the study, of which 3 were from infection concurrent with neutropenia.13
Included within this study of rituximab accompanying chemotherapy in MCL was an analysis of potentially prognostic factors in this disease. This found that serum levels of b2-microglobulin, a component of the major histocompatibility complex that is present on the surfaces of various cells, and which the immune system uses to distinguish the body's own cells from "non-self"or alien cells, predicted relapse-free survival for the overall study group of patients and for those over age 65, but not for younger patients.13 Clinically, the findings of the study led the clinicians who conducted it to conclude that rituximab added to both the hyper-CVAD regimen and to the high-dose combination of methotrexate with cytarabine is effective against previously untreated aggressive MCL, producing prolonged remissions in patients aged 65 and younger, and that the relapse-free survival rate of 73% at a 3-year follow-up compared favorably with that for high-dose chemotherapy followed by stem-cell transplantation in aggressive MCL.13 However, the study concluded that a further and more complete comparison of its treatment regimen would be needed to more fully determine the role in treatment outcome of variations in patient characteristics, differences in the treatment regimens, and other variables.13
Rituximab With Chemotherapy in the
Treatment of Indolent Follicular Lymphoma.
Among the diverse group of hematologic malignancies defined as NHL,1 are the diseases known as indolent lymphomas, which arise in clones of B lymphocytes.14 Although associated with relatively long periods of survival14 and showing high overall rates of response to chemotherapy, indolent NHL is characterized by continuous relapse,15 and although radiotherapy can be curative in a small proportion of patients with very localized disease,16 the overwhelming number of cases are incurable with any current treatment.14
Constituting approximately 70% of all cases of indolent lymphoma and 20% to 25% of all cases of NHL, the most frequent indolent lymphoma is follicular lymphoma.17 Patients with this disease, which is marked by small, large, or mixed small and large Bcells with a "cleaved" appearance in the peripheral circulation, may live for years without requiring treatment.1 Radiation therapy, the established treatment for early-stage follicular lymphoma, provides 10-year survival in 64% to 80% of cases,18 but the majority of patients have advanced, stage III or IV disease at the time of diagnosis, and despite a high rate of responsiveness to initial chemotherapy, most die after a series of treatment-induced remissions followed by relapses.15,19 The median survival after the diagnosis of follicular lymphoma ranges from 6 to 10 years.16,19 Because there is no evidence that the early treatment of asymptomatic, late-stage follicular lymphoma improves survival, such disease is often managed with monitoring alone until the appearance of symptomatic disease,19,20 which is typically marked by a persistent, diffuse, and painless lymphadenopathy.21
No uniform first-line treatment exists for symptomatic, advanced follicular lymphoma. Treatment often begins with chlorambucil as a single agent, or with the combination of cyclophosphamide, vincristine, and prednisone (CVP)19,22 or CHOP.22 As a first-line approach to the disease, such treatment is typically highly effective, yielding complete responses in 37% to 81% of cases,23-28 and response rates with the CVP regimen have ranged from 60% to 80%. However, the median duration of response has been less than 2 years.19 Anthracyclines do not appear to improve the outcome of treatment of follicular lymphoma, and have substantial toxicity.19 Interferon-a (IFN-a) can increase the frequency and duration of response when used in conjunction with chemotherapy, but has side effects that many patients cannot endure.19 Nucleoside analogs such as fludarabine have shown promise in treating follicular lymphoma, but their benefit has not been shown to surpass that of existing treatments.19
Within the past 5 years, steadily increasing numbers of patients with follicular lymphoma have been treated with newer agents in combination with such established modalities as chemotherapy, irradiation, or stem-cell transplantation.16 One of the most widely investigated of such newer agents has been rituximab, a recombinant, humanized monoclonal antibody directed at the CD20 surface antigen present on lymphocytes.10,19 Rituximab has been shown to promote the lytic destruction of CD20-bearing lymphoma cells through complement-mediated cytotoxicity, ADCC, and apoptosis, and has been active both alone and in combination with chemotherapy in treating indolent and aggressive forms of NHL.10,19 When used as a single treatment agent in recurrent low-grade follicular lymphoma or disease that has proven refractory to other treatment, rituximab has been shown to produce overall response rates approximating 50%, with responses lasting a median of about 1 year.1,29 A study conducted in 2001 found that its use as a single agent for the first-line treatment of follicular lymphoma produced responses in 73% of patients, a figure marginally better than that achieved with chemotherapy.30 When combined with some cytotoxic chemotherapeutic agents, rituximab has shown synergistic effects,31 and in vitro studies have suggested that it can sensitize lymphoma cell lines to chemotherapy.32
Over the past 5 years, the finding in a number of studies of overall response rates of 81% to 97% with responses lasting from about 32 to 36 months, as well as improvements in other outcome measures, have made the combination of rituximab with the CVP (R-CVP) or R-CHOP the standard of care for advanced follicular lymphoma.1,19
A recent German study comparing CHOP with R-CHOP in 428 patients with untreated advanced follicular lymphoma found a 60% lower relative risk for treatment failure, response rate of 96% versus 90%, and superior overall survival, with 6 deaths versus 17 deaths at 3 years with the R-CHOP regimen.33 Although severe granulocytopenia was more often observed with the R-CHOP regimen, at 63%, versus 53% for CHOP alone, severe infections were of comparable frequency in both groups, at 5% and 7%, respectively.33 The study concluded that adding rituximab to the CHOP regimen significantly improves outcomes in previously untreated follicular lymphoma, without having major adverse effects.33
In a more recent, multicenter international study comparing the R-CVP with the CVP regimen in 322 patients with untreated stage III/IV follicular lymphoma,19 the rituximab-containing regimen produced overall and complete response rates of 81% versus 57% and 41% versus 10%, respectively. At a follow-up of 30 months, patients treated with the RCVP regimen had had a significantly longer time to treatment failure, of 27 months versus 7 months in the CVP arm, and a median survival of more than twice that with the CVP regimen, at 32 versus 15 months. Although the median period of disease-free survival in the R-CVP arm of the study had still not been reached at 30 months, it had been established as 21 months in the CVP arm.19
In this study, rituximab did not significantly add to the toxicity of the CVP regimen, and the percentages of patients reporting at least one adverse event during the course of treatment was closely similar, at 97% in the R-CVP group and 95% in the CVP group. The most frequent adverse events seen in the R-CVP arm of the study were associated with the gastrointestinal and nervous systems. The most severe events in this arm were grade 3 or 4 neutropenia, fatigue, and back pain, which were slightly more common than in the CVP arm of the study.19
In this randomized trial, the addition of rituximab to the CVP regimen produced gains in all major end point measures of treatment efficacy in patients with previously untreated and advanced follicular lymphoma. The gain in time to disease progression resulting from the addition of rituximab to the CVP regimen was similar to that observed with more intensive combination regimens of IFN with anthracycline-containing regimens, but without these regimens' toxicity.19
Another, recently reported trial evaluated the ability of 2 years of maintenance rituximab to prolong disease-progression-free survival after treatment with the CVP regimen or with the combination of cyclophosphamide and fludarabine in patients with stage III/IV follicular lymphoma.16
Although 516 patients were originally randomized to receive treatment with one of the two regimens, the combination of cyclophosphamide and fludarabine was discontinued because of toxicity before the study ended.16 Of 401 patients in the CVP group who were treated to the point of maximum response, 322 of those whose disease responded were allocated to receive rituximab in 4 weekly doses every 6 months or to observation without treatment. The study was concluded before its planned termination when it was found that 74% of patients treated with rituximab had survived without disease progression at 2.5 years after treatment, as opposed to 42% of those in the observation group, and that NHL had still not progressed in 58% of the rituximab-treated patients after 4 years, as opposed to a corresponding figure of 34% in the observation group.16
The investigators conducting the study concluded that maintenance therapy with rituximab following CVP chemotherapy significantly prolongs survival without disease progression in advanced indolent NHL.16
Despite these benefits of rituximab, relapse inevitably continues to follow disease-free periods of 15 months to 3.6 years after chemotherapy with or without rituximab in follicular lymphoma.27,34,35
Besides prolonged maintenance therapy, strategies being investigated for improving the efficacy of rituximab in NHL have increase in dose through extended induction schedules.10 Moreover, while the advent of targeted monoclonal antibodies represents a major advance from cytotoxic chemotherapy for follicular lymphoma and other forms of NHL, treatment agents with greater tumor specificity and lower toxicity are needed.1 Efforts in this direction have involved studies with novel antibodies and biologic agents, such as the radioisotope-bearing anti-CD20 monoclonal antibodies ibritumomab tiuxetan and tositumomab, with the goal of delivering these isotopes directly to B-lymphocytes,1,10 and the recent study of vaccines containing anti-idiotype proteins derived from a patient's malignant B-lymphocytes with the goal of promoting an attack against tumor cells by the patient's own immune system.1
1. Vose JM. Personalized immunotherapy for the treatment of non-Hodgkin's lymphoma: a promising approach. 2006 (In press).
2. The Merck Manual of Diagnosis and Therapy. Section 11, Hemotology and oncology, Chapter 139, Lymphomas. Available at: http://www.merck.com/mrkshared/ mmanual/section11/chapter139/139a.jsp. Accessed March 1, 2006.
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5. Rigacci L, Nassi L, Alternini R, et al. Dose-dense CHOP plus rituximab (R-CHOP14) for the treatment of elderly patients with high-risk diffuse large B-cell lymphoma. 2006;115:22-27.
6. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP Study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. 2005;23:4117-4126.
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7. Tirelli U, Errante D, Van Glabbeke M, et al. CHOP is the standard regimen in patients Â³ 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group. 1998;16:27-34.
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14. McLaughlin P. Progress and promise in the treatment of indolent lymphomas. 2002;7:217-225.
15. Hochster HS, Weller E, Ryan T, et al. Results of E1496: a phase III trial of CVP with or without maintenance rituximab in advanced indolent lymphoma (NHL). American Society of Clinical Oncology 2005 Annual Meeting [Abstract 6502]. Available at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=26&abstractID=1337. Accessed March 1, 2006.
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30. Colombat P, Sales G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. 2001;97:101-106.
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32. Demidem A, Lam T, Alas S, et al. Chimeric anti-CD20 (IDEC-C288) monoclonal antibody sensitizes B-cell lymphoma line to cell killing by cytotoxic drugs. 1997;12:177-186.
33. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly 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. 2005;106:3725-3732.
34. Hiddemann W, Dreyling M, Forstpointner R, et al. Combined immuno-chemotherapy (R-CHOP) significantly improves time to treatment failure in first-line therapy of follicular lymphomaâ€”results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). 2003;102. [Abstract 352].
35. Marcus R, Imrie K, Belch A, et al. An international, multi-centre, randomized, open-label phase III trial comparing rituximab added to CVP chemotherapy to CVP chemotherapy alone in untreated stage III/IV follicular non-Hodgkin's lymphoma2003;102 [Abstract 87].