The first attempt at using monoclonal antibodies in lymphoma therapy, reported in 1980, was unsuccessful. Since that time, several immunotherapeutic approaches to treating non-Hodgkin’s lymphoma have been developed,
Dr. Vose has provided an excellentoverview of the immunotherapeutic options currently available, or that will soonbe available, for the clinical management of patients with non-Hodgkin’slymphoma (NHL). These new options present the clinical oncologist with a dilemmaas to which is most efficacious in a given clinical situation, and in what orderthey should be administered over a patient’s clinical course. Among theseoptions are the use of unlabeled monoclonal antibodies, radiolabeled antibodies,and tumor-specific idiotype vaccination.
I believe it is important to validate each of these newtreatments on their individual ability to cause disease regression. However, itis also likely that ultimately they will have the greatest impact when combinedwith or administered following conventional therapies. We need to continue tomove from single-agent clinical trials to trials of rational combinations orsequences that may provide a survival advantage, but as Dr. Vose points out,this will require results from prospective randomized phase III trials.
The explosive use of the chimeric anti-CD20 antibody rituximab(Rituxan) in clinical oncology is instructive of this process. Phase I/II trialsdemonstrated that the antibody was safe and caused tumor regression in patientswith a variety of B-cell histologies.[1-3] Response rates to single-agenttherapy were generally higher in patients with follicular NHL and in patientswho had received less prior therapy. However, responses were also seen whenrituximab was administered as a single agent in patients with relapsedaggressive NHL.
While responding patients have obviously benefited, there havenot been any single-agent trials that demonstrate changes in survival.Nevertheless, the lack of serious side effects allowed combination trials withchemotherapy, and several small studies have demonstrated that rituximab may begiven with or following standard CHOP chemotherapy (cyclophosphamide [Cytoxan,Neosar]/doxorubicin HCl/vincristine [Oncovin], prednisone), without compromisingthe chemotherapy dose or altering the toxicity.[5,6]
Data from these trials suggest a high response rate and apromising length of remission but do not demonstrate that rituximab plus CHOP isbetter than CHOP alone. The results of an interim analysis presented at the 2000meeting of the American Society of Hematology by Dr. Bertrand Coiffier on behalfof the Groupe d’Etude des Lymphomes de l’Adulte (GELA) provided the firstglimpse of evidence that the combination of CHOP and rituximab is superior toCHOP alone in elderly patients with aggressive NHL. The combination was superiorin terms of remission induction rates as well as 1-year disease-free and overallsurvival.
The early and preliminary results of this trial are exciting butthreaten to halt the progression of critical ongoing trials that are evaluatingrituximab in other combinations and clinical situations. It is important thatthe confirmatory trials are properly evaluated and that data from these trialsmature and are published. Hopefully, these trials will confirm the findings fromGELA.
Ongoing trials in other histologies, such as low-grade NHL,should be completed to determine the effects of combined therapy in diseasesthat are associated with a continuous pattern of relapse.
Several new agents that utilize either iodine-131 or yttrium-90to provide targeted radiation to B-cell tumors expressing the CD20 antigen arein the late stages of clinical trials. These agents appear to have greaterantitumor effects as single agents than as unlabeled anti-CD20 antibodies,although with increased toxicity.[8,9]
It is important to note that all radiolabeled antibodies havesignificant dose-limiting toxicity, and that that toxicity may be dependent onthe patient’s tumor burden. In most cases, this involves bone marrowsuppression, making combination studies with these agents and standardchemotherapy difficult. Sequential administration or the use of stem cellsupport may alleviate this complication.
The induction of an antitumor immune response in a patient mayfoster more selective antitumor activity. Data from several small phase I/IItrials evaluating this approach in follicular NHL patients followingchemotherapy suggest that immune responses may be generated, and thatsuccessfully immunized patients who are in remission have a low relapserate.[10,11] Ongoing phase III trials are necessary to validate these findings.Also, it remains to be determined if recent technological advances make acustomized treatment approach feasible.
The availability of these new agents and the lack of clearclinical trial results to guide proper combinations or sequences will presentchallenges for the management of lymphoma patients. For example, the inductionof an idiotype-specific immune response may be difficult in patients who havebeen recently treated with anti-CD20 antibodies, because of the transientdepletion of B cells. Likewise, the induction of a human antimouse antibodyresponse to a murine antibody may preclude subsequent treatment with anothermurine antibody later in the course of a patient’s disease.
Studies should continue to compare these promising approachesdirectly in prospective clinical trials. It is gratifying to see immunotherapyemerge into the clinical arena for lymphoma therapy. Hopefully, these advanceswill improve long-term cure rates and decrease treatment toxicities for lymphomapatients as well as for those with other malignancies.
1. Maloney DG, Liles TM, Czerwinski DK, et al: Phase I clinicaltrial using escalating single-does infusion of chimeric anti-CD20 monoclonalantibody (IDEC-C2Ba) in patients with recurrent B-cell lymphoma. Blood84:2457-2466, 1994.
2. Malney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8(Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsedlow-grade non-Hodgkin’s lymphoma. Blood 90:2188-2165, 1997.
3. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximabchimeric anti-CD20 monoclonal antiobody therapy for relapsed indolent lymphoma:Half of patients respond to a fou-dose treatment program. J Clin Oncol16:2825-2533, 1998.
4. Cooiffier B, Haioun C, Ketterer N, et al: Rituximab(anti-CD20 monoclonal antibody) for the treatment of patients with relapsing orrefractory aggressive lymphoma: A multicenter phase II study. Blood92:1927-1932, 1998.
5. Czuczman MS, Grillo-Lopez AJ, White CA, et al: Treatment ofpatients with low-grade B-cell lymphoma with the combination of chimericanti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268-276,1999.
6. Vose JM, Link BK, Grossbard ML, et al: Phase II study ofRituximab in combination with chemotherapy in patients with previouslyuntreated, aggressive non-Hodgkin’s lymphoma. J Clin Oncol 19:389-397, 2001.
7. Coiffier B, Lepage E, Herbrecht R, et al: Mabthera(Rituximab) plus CHOP is superiour to CHOP alone in elderly patients withdiffuse large B-cell lymphoma: Interim results of a randomized GELA trial(abstract 950). Blood 96(11):223a, 2000.
8. Vose JM, Wahl RL, Saleh M, et al: Multicenter phase II studyof iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade andtransformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol18:1316-1323, 2000.
9. Wiseman GA, White CA, Witzig TE, et al: Radioimmunotherapy ofrelapsed non-Hodgkin’s lymphoma with zevalin, a 90Y-labeled anti-CD20monoclonal antibody. Clin Cancer Res 5:3281s-3286s, 1999.
10. Hsu FJ, Caspar CB, Czerwinski D, et al: Tumor-specificidiotype vaccines in the treatment of patients with B-cell lymphoma: Long-termresults of a clinical trial. Blood 89:3129-3135, 1997.
11. Bendandi M, Gocke CD, Kobrin CB, et al: Complete molecularremissions induced by patient-specific vaccination plus granulocyte-monocytecolony-stimulating factor against lymphoma (see comments). Nat Med 5:1171-1177,1999.