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Home , ABVD, Chemotherapy regimen, Hodgkin lymphoma, MOPP (chemotherapy), Oblimersen

The and Group B Committee Bruce D. Cheson1and George P. Canellos2

Abstract The malignant include at least 30 entities that are distinct with respect to , immunology, genetics, clinical features, and outcome following . The clinical behavior of these diseases ranges from indolent but generally incurable to aggressive and frequently fatal yet potentially curable with appropriate or chemotherapy-antibody regimens. Over the past 50 years, the Cancer and Leukemia Group B (CALGB) Lymphoma Committee has con- ducted a series of clinical trials that have contributed to an improvement in outcome for patients with a number of the more common lymphoma subtypes.

The World Health Organization has classified approximately therapy alone. Although plays less of a role in 30 neoplastic diseases of the hematopoietic and lymphoid the current management of this subgroup of patients given the tissues (1). The Cancer and Leukemia Group B (CALGB) greater efficacy of contemporary chemotherapy regimens, this Lymphoma Committee highlight below clinical trials that have study provided important information about the use of resulted in improved patient outcome for the more frequent combined modality treatment at the time it was published. lymphoma subtypes. The mechlorethamine, , , and procar- bazine (MOPP) combination provided the first evidence for cure in a substantial proportion of Hodgkin’s Lymphoma patients with stage III and IV Hodgkin’s lymphoma. Never- Hodgkin’s lymphoma represents one of the successes of theless, over the decades since the introduction of MOPP, modern . Patients with limited stage disease were other regimens were developed to improve on the efficacy of traditionally treated with radiation therapy as the primary MOPP while attempting to reduce its toxicities, particularly modality. Although the majority of patients were cured, systemic infertility and secondary malignancies (4–8). Nissen et al. (7) therapy was required for those that developed a recurrence. conducted a randomized study comparing MOPP with several CALGB investigators (2) conducted a randomized trial in 113 modifications of the MOPP regimen; in one, 1,3-bis(2- patients whose disease had progressed after primary radiation chloroethyl)-1- was substituted for the nitrogen therapy. The study involved a comparison among 1-(2-chlor- mustard (BOPP), another eliminated the (MOP), oethyl)-3-cyclohexyl-L-nitrosourea, , procarbazine, and another omitted the alkylating agent (OPP). The three drug , prednisone; Adriamycin, , vincristine, combinations were clearly inferior with respect to response and ; and a regimen that alternated between the rate and survival. BOPP and MOPP were comparable, although two regimens. Although there were no major differences in the former was felt to have less treatment-associated toxicity. efficacy among the various treatment strategies, an important Other regimens substituting 1-(2-chloroethyl)-3-cyclohexyl-L- observation was that almost half of the patients remained failure nitrosourea for or vinblastine for vincristine free at 5 years, and 60% remained alive. were highly effective but with considerable hematotoxicity (8). Currently, most patients who present with advanced-stage Based on the work of Bonadonna et al., the Adriamycin, disease can be cured with conventional doses of multiagent bleomycin, vinblastine, and (ABVD) and MOPP/ chemotherapy. For those with stage III disease, chemotherapy ABVD regimens received considerable interest (9, 10). However, plus radiotherapy was often used, although the optimal approach their efficacy compared with the standard MOPP regimen was poorly defined. CALGB investigators conducted a small trial remained to be determined. CALGB conducted a pivotal in which patients with stage III disease were randomized to four comparison of MOPP, ABVD, and MOPP/ABVD (11). The study weekly doses of vinblastine and one dose of mechlorethamine included 361 eligible patients and reported an overall response hydrochloride followed by no additional therapy involved field rate of 93%, including 77% complete remissions; both complete radiation therapy or total nodal irradiation (3). The patients were and overall response rates favored the containing followed to a maximum of 10 years. The combined modality regimens. Moreover, the failure-free survival at 5 years was 50% approaches produced a longer disease-free survival than chemo- for MOPP, 61% for ABVD, and 65% for MOPP-ABVD. In addition, MOPP was associated with greater toxicities and, as a result of this trial, was virtually abandoned as initial chemo- Authors’ Affiliations: 1Georgetown University Hospital, Washington, District of therapy for Hodgkin’s lymphoma. Subsequent data on a MOPP/ Columbia and 2Dana-Farber Cancer Institute, Boston, Massachusetts ABV hybrid regimen were sufficiently encouraging to lead to a Requests for reprints: Bruce D. Cheson, Division of /Oncology, subsequent trial of ABVD versus the MOPP/ABV hybrid (12, 13). Georgetown University Hospital, 3800 Reservoir Road, Northwest, Washington, The two regimens showed comparable efficacy; however, the DC 20007. E-mail: bdc4 @georgetown.edu. F 2006 American Association for Cancer Research. lower toxicity with ABVD, especially with regard to acute doi:10.1158/1078-0432.CCR-06-9003 pulmonary and hematologic toxicity and second malignancies,

Clin Cancer Res 2006;12(11Suppl) June 1, 2006 3572s www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2006 American Association for Cancer Research. The CALGB Lymphoma Committee established ABVD as the current standard chemotherapy therapy High-Grade NHL for patients with advanced-stage Hodgkin’s lymphoma (14). Burkitt’s leukemia is rare but may manifest as a highly Follicular Non-Hodgkin’s Lymphoma aggressive form of acute lymphoblastic leukemia (L3). In addition, a small fraction of adult lymphomas are of the small Before the introduction of , no evidence supported noncleaved morphology. Based on data from pediatric trials the use of one chemotherapy regimen over another in the suggesting benefit from high-intensity, short-course chemo- treatment of patients with follicular or low-grade non- therapy in patients with this histology, the CALGB conducted Hodgkin’s lymphoma (NHL). Moreover, considerable contro- protocol 9251 (25). The patient population included 24 versy existed as to whether initial combination chemotherapy patients with acute lymphoblastic leukemia and 51 patients was superior to treatment with a single alkylating agent. In a with small noncleaved NHL. They were treated with an prospective trial, CALGB randomly assigned 228 patients to intensive multiagent regimen, including either oral cyclophosphamide at 100 mg/m2/d or cyclophos- and prednisone followed by , high-dose methotrex- phamide-Adriamycin-vincristine-prednisone (CHOP)/bleomy- ate, vincristine, , doxorubicin, , cytar- cin for 2 years or until toxicity was prohibitive. In the latter abine, and central nervous system prophylaxis with either triple regimen, bleomycin was discontinued at a cumulative dose of intrathecal therapy or central nervous system irradiation. Of the 60 units/m2, and the Adriamycin was discontinued after 450 54 eligible patients, 43 attained a complete remission, and 28 mg/m2. With 20 years of follow-up, failure-free and overall (52%) were alive and in continuous complete remission with a survival were comparable between the arms. In an unplanned median follow-up of 5.1 years. The original regimen was subset analysis, patients with what was then called follicular associated with considerable neurotoxicity related to the mixed lymphoma experienced a longer survival with the radiation and was subsequently modified to reserve cranial combination regimen. However, this finding has not been irradiation for patients with or central nervous consistently observed in other studies. Nevertheless, the system disease, begin irradiation after completion of chemo- prolonged follow-up reported in this study clearly showed therapy, and reduce the number of doses of intrathecal that more intensive treatment did not necessarily confer chemotherapy. Evaluation of a subsequent cohort of patients meaningful clinical benefit in these diseases, similar to other suggested that the frequency and severity of neurologic reports (15, 16). toxicities was substantially decreased (26).

Diffuse Large B-Cell Lymphoma Current Studies and Future Directions

For decades, the CHOP regimen had been the standard The CALGB Lymphoma Committee is pursuing a number therapy for patients with previously untreated, advanced-stage of novel directions in its clinical trials. The Committee is diffuse large B-cell lymphoma (17). Numerous attempts were committed to testing new chemotherapy regimens in patients made to improve on the efficacy of this combination by adding with Hodgkin’s lymphoma. Although >90% of patients with other agents that were presumed to be non–cross-resistant and low-risk disease may be cured with radiation or combination with nonoverlapping toxicities (18–20). The CALGB developed chemotherapy, there are long-term toxicities associated with one such regimen in which the dose of and the these approaches. has been shown to have a high role of bleomycin were evaluated in the context of the other level of activity in patients with relapsed and refractory agents in CHOP (21). In CALGB 7851, 177 patients with diffuse Hodgkin’s lymphoma and is thus a potentially important agent large B-cell lymphoma and 97 with other aggressive for the initial treatment of this disease (27). The Committee received three cycles of CHOP every 3 weeks with or without developed a combination of doxorubicin, vinblastine, and bleomycin. Those patients who experienced a response were gemcitabine that is being used as the initial therapy of low-risk randomized for the next three cycles to receive high-dose patients. The role of positron emission tomography will also be methotrexate with leucovorin rescue or to no additional the- evaluated in this trial. In relapsed patients, the Committee is rapy. There was no benefit to the addition of either bleomycin or building on its encouraging prior results with a regimen high-dose methotrexate. Other combinations were studied in composed of liposomal doxorubicin, , and gemci- patients who were refractory to CHOP or similar regimens (22). tabine, which achieved responses in 58% of relapsed and These data suggested that the addition of other drugs would not refractory patients who had not received a prior autologous add to the activity of CHOP as had already been proposed (23). stem cell transplant and in 68% of those who had progressed Further confirmation of the role of CHOP was provided by a after that procedure. The new protocol uses the same national high-priority trial in which the CALGB participated with chemotherapy but also incorporates an anti-CD30 monoclonal the Southwest Oncology Group; CHOP was compared with antibody (28). Although the single-agent data with such methotrexate, bleomycin, Adriamycin, cyclophosphamide, vin- antibodies in Hodgkin’s lymphoma has been modest, the cristine, dexamethasone (MACOP-B); methotrexate, Adriamycin, expectation is that it will enhance the activity of the cyclophosphamide, vincristine, prednisone, bleomycin chemotherapy agents (29, 30). (MACOP-B); and prednisone, methotrexate, Adriamycin, cyclo- Protocols evaluating doublets of biological agents without phosphamide, etoposide, , bleomycin, vincristine, chemotherapy are actively accruing previously untreated methotrexate (ProMACE/CytoBOM). Outcomes with the various patients with follicular NHL. The first of these combinations regimens were similar, except with less toxicity in the CHOP is rituximab and the anti-CD80 monoclonal antibody arm, further establishing CHOP as the standard of care for galiximab based on encouraging phase II data in previously patients with aggressive NHL(24). treated patients (31). Upon completion of this trial, the next

www.aacrjournals.org 3573s Clin Cancer Res 2006;12(11Suppl) June 1,2006 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2006 American Association for Cancer Research. doublet will be rituximab and , a bcl-2 antisense One of the most promising new agents in the treatment of oligonucleotide that adds to the activity of other agents in is the bortezo- lymphoid malignancies (32). Studies of new agents will also mib, which induces responses in 30% to 50% of patients with be conducted in patients with relapsed . relapsed or refractory disease (37, 38). Following encouraging An agent of interest is , a second-generation results with an intensive front-line strategy, including ritux- immunomodulatory agent with activity in patients with 5qÀ imab and autologous stem cell transplantation, CALGB has (33), , and decided to incorporate into the treatment strategy chronic lymphocytic leukemia (34). To date, there are no (39). Response rates to any one of a variety of chemotherapy data in patients with NHL. The current CALGB protocol for regimens are high in mantle cell lymphoma; however, the patients with follicular NHLwho have relapsed after durability of such responses is disappointing. Therefore, the chemotherapy plus rituximab is a randomized study of either current front-line protocol for patients with mantle cell rituximab as a single agent, lenalidomide, or a combination of lymphoma will test the optimal delivery schedule for borte- the two drugs. zomib as a maintenance strategy. For patients who progress Diffuse large B-cell lymphoma can be distinguished into three after an initial therapy, the doublet of lenalidomide and genetically distinct subtypes by microarray analyses (35). bortezomib is being evaluated. In addition, a phase I/II prog- Molecular profiling may also be used to identify appropriate ram is under development that will focus on new proapop- therapy for select patients. Thus, the current CALGB study for totic agents in patients with refractory lymphomas of various previously untreated patients with diffuse large B-cell lymphoma histologies. involves a comparison between R-CHOP and the infusional R- A major goal of the Committee is to incorporate a correlative EPOCH regimen developed by National Cancer Institute or translational research study into every protocol. All patients investigators (36). However, the critical questions in this study entered onto the diffuse large B-cell protocol (CALGB 50303) will be addressed by DNA microarray analyses on will undergo core for fresh frozen tissue to samples from all patients. These include a prospective validation be submitted for DNA microarray analysis. For protocols of the prognostic subsets of diffuse large B-cell lymphoma, to involving other histologies, tissue microarrays are being assess the use of molecular profiling for pathologic diagnosis, prepared, and samples of genomic DNA from peripheral blood identification of the molecular signature patterns that correlate mononuclear cells are being collected to correlate receptor best with outcome following either infusional R-EPOCH or polymorphisms with clinical outcome. By emphasizing the bolus R-CHOP therapy and to potentially identify new importance of correlative science, the Committee hopes to therapeutic targets using molecular profiling. better understand the biology of the various histologic and The treatment of patients with mantle cell lymphoma has biological subtypes of malignant lymphoma and to more been frustrating, with high response rates to standard chemo- rationally develop treatment strategies, leading to an improved therapy regimens but eventual relapse in virtually all patients. outcome for patients with these diseases.

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Bruce D. Cheson and George P. Canellos

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