Rituximab:  The First Monoclonal Antibody Approved for the Treatment of Lymphoma

A.J. Grillo-López*, C.A. White, B.K. Dallaire, C.L. Varns, C.D. Shen, A. Wei, J.E. Leonard, A. McClure, R. Weaver, S. Cairelli and J. Rosenberg

IDEC Pharmaceuticals Corporation, 3030 Callan Road, San Diego, California 92121, USA

 

*Address correspondence to this author at the Medical & Regulatory Affairs, IDEC Pharmaceuticals Corporation, 3030 Callan Road, San Diego, CA  92121, U.S.A.; Tel.:  (858) 431-8500; Fax:  (858) 431-8889; E-Mail: agrillo@idecpharm.com

 

Abstract:  Rituximab, a genetically engineered monoclonal chimeric antibody, targets the CD20 antigen expressed on B cells.  It was approved by the US Food and Drug Administration on November 26, 1997, for the indication of relapsed or refractory, CD20-positive, B‑cell, low-grade or follicular non-Hodgkin’s lymphoma (LG/F NHL), and by the European Agency for the Evaluation of Medicinal Products on June 2, 1998, for therapy of patients  with Stage III/IV, follicular,  chemoresistant or relapsed NHL. Eight Phase II or III clinical trials in LG/F NHL patients have been completed:  five single‑agent studies and three combination studies.  Rituximab has a favorable safety profile: most adverse events (AEs) are Grade 1 or 2, and the frequency of AEs decrease with subsequent infusions.  AEs in the combination studies are consistent with those seen with individual agents.  For evaluable patients in the single‑agent studies, overall response rates (ORR) ranged from 40% to 60%, median duration of response (DR) ranged from 5.9 to 15.0+ months, and median time to progression (TTP) ranged from 8.1 to 19.4+ months.  For evaluable patients in the combination studies, the ORR ranged from 45% to 100%, median DR ranged from 11.7+ to 39.1+ months, and median TTP ranged from 12.9+ to 40.5+ months.  Studies in intermediate- and high-grade NHL are ongoing.  Long‑term development plans include evaluating the safety and efficacy of rituximab in various types of lymphoma and in combination with other lymphoma regimens. Future studies may explore ways to increase rituximab efficacy by upregulating CD20 or increasing effector function with different cytokines.

Introduction

     Rituximab is a human IgG1 kappa antibody with mouse variable regions isolated from a murine anti-CD20 antibody (IDEC-2B8), as illustrated in Fig. (1).  This chimeric antibody was developed at IDEC Pharmaceuticals Corporation, San Diego, CA, through: immunization of BALB/c mice with the CD20+ human lymphoblastoid cell line SB; isolation of the murine anti-CD20 antibody IDEC-2B8; cloning and sequencing of the murine variable region; construction of the chimeric anti-CD20 Ig DNA expression vector through genetic engineering; and manufacturing of Chinese hamster ovary (CHO) cells as rituximab producing transfectoma [1].

Fig. (1).  Diagram of the chimeric antibody rituximab.

     Rituximab binds with high affinity (approximately 8.0 nM) to cells expressing the CD20 antigen found on the surface of malignant and normal B cells, but not on other normal tissues [2]. The antibody maintains the specificity and affinity for the target antigen equivalent to that of the native murine parent, IDEC-2B8. In vitro mechanism of action studies demonstrated that this antibody binds human complement and lyses lymphoid B‑cell lines (CDC), lyses human target cells through antibody-dependent cellular cytotoxicity (ADCC)[1], induces apoptosis in human lymphoma cell lines [3, 4], induces tyrosine phosphorylation [4], and inhibits cell proli-feration [4].

     The CD20 antigen is expressed in the majority of B-cell lymphomas; in a series of 151 patients with B-cell non-Hodgkin's lymphoma, 93% of tumors expressed the CD20 antigen [5].  It appears to play an important role in the process of B-cell differentiation and may control B lymphocyte progression through the cell cycle [6-9].  The CD20 antigen is a potential calcium ion channel [10] and may be involved in the regulation of signal transduction [11]. This antigen arises during the pre‑B-cell stage of B‑cell development [12].  Since the formation of stem cells and pre‑pre-B (or pro-B) cells is an earlier step in this process, treatment with rituximab does not affect either stem cells or pre-pre B-cell development.

     Furthermore, the CD20 antigen is not present on plasma cells and dendritic cells. Thus, following depletion, a normal B-cell population can be reconstituted from unaffected precursor cells while antibody production continues from the normal plasma cell pool.

     The CD20 antigen is a suitable target for the treatment of B‑cell lymphomas because it does not circulate in the plasma as free protein [13], it does not shed from the surface of CD20 positive cells after binding of the anti-CD20 monoclonal antibody [14], and it does not internalize upon antibody binding [14].

     The clinical use of a chimeric antibody rather than a murine monoclonal antibody has three potential advantages. First, reduced immuno-genicity permits repeated administration [15, 16].  Second, a chimeric antibody has a longer half-life that produces a prolonged effect even after low doses compared with a murine antibody [15, 17, 18]. Finally, a chimeric antibody, because of its human constant regions, induces human effector functions including complement-dependent cytotoxicity (CDC) and ADCC[1].

     Pre-clinical studies were conducted in cynomolgus monkeys to evaluate the pharmacokinetics, safety, immunogenicity, and B-cell-depleting potency of rituximab [1].  Depletion of peripheral blood B cells was evaluated in four animals treated with total doses of 0.04 to 6.4 mg/kg of rituximab over four days.  Total doses between 0.4 and 6.4 mg/kg depleted greater than 95% of peripheral blood B cells for as long as 8 days postinfusion.  Disappearance of rituximab-coated cells followed B cell depletion.  After Day 8, the B cells began a slow recovery. Recovery occurred more rapidly in some monkeys than others and appeared to be dose dependent. Four cynomolgus monkeys, divided into two dose groups, were given a single dose of either 1.6 or 6.4 mg/kg of rituximab to evaluate B-cell depletion in lymph nodes 15 and 29 days postinfusion.  B‑cell depletion in the lymph nodes varied widely among individuals and between dose groups (34% to 78%).  Most of the depletion occurred before day 15 with little regeneration within the first 30 days.  High-dose studies of four cynomolgus monkeys given four weekly doses of 16.8 mg/kg showed that, at 22 days postinfusion, lymph node B-cell populations were 84% to 87% lower than in the control monkey.  At the same timepoint, lymph node T‑cell populations were 85% to 90% of total lymphocytes in treated monkeys and 52% of total lymphocytes in the control monkey.  No weight loss or other visible effects of antibody treatment other than loss of B cells were noted.

     The clinical development of rituximab was conducted by IDEC Pharmaceuticals Corporation, San Diego, California.  See Fig. (2). IDEC began collaborations with Genentech Inc., San Francisco, California, in March 1995, for the manufacturing, marketing, and sales of rituximab in the United States.  Shortly thereafter, collaborations began with F. Hoffmann-La Roche Ltd., Basel, Switzerland, for the development of rituximab in the European Union, and with Zenyaku Kogyo Co., Ltd, Tokyo, Japan, for the development of rituximab in Japan.  Results from eight Phase II or III studies conducted in low-grade or follicular non-Hodgkin’s lymphoma (LG/F NHL) are presented here.

Fig. (2).  Clinical development of rituximab.

Response Criteria for NHL

     Standard criteria exist for the evaluation of the clinical response in patients with solid tumors [19], chronic lymphocytic lymphoma (CLL) [20], Hodgkin’s disease (HD) [21], and acute  leukemias [22].  Until recently, specific criteria did not exist for the evaluation of response in patients with NHL; rather, criteria for solid tumors developed by the World Health Organization [19] and the Eastern Cooperative Oncology Group [23] were used.  After consultation with the U.S. Food and Drug Administration (FDA), a panel of three lymphoma experts (Drs. Horning, Peterson, and Cheson) was convened in December 1995 and subsequently produced a consensus statement in which they defined response criteria for LG/F NHL to be applied in the pivotal clinical trial of the anti-CD20 antibody rituximab [24]. These response criteria included response classifications (Table 1), measures of duration, definitions of measurable lesions and measurable disease, procedures for lesion measurement, and a quality assurance process for response data.  The response criteria were reviewed and accepted by the FDA and were endorsed by a group of European NHL experts that included Drs. Coiffier, Hagenbeek, Hiddemann, Marcus, Lister, Gianni, and García‑Conde [25].

     The response criteria were applied to the data of the 166-patient pivotal trial of rituximab at each site by the principal investigator [26, 27].  Then, an independent audit of computed tomography scans at baseline, onset of response, and confirmation of response for all patients exhibiting a 40% or greater reduction in overall tumor size was conducted as a quality assurance measure and as confirmation of the clinical investigator’s assessment of response.  The audit was conducted by a Lymphoma Expert’s Confirmation of Response (LEXCOR) panel that consisted of six hematologists/oncologists and three radiologists, all recognized lymphoma experts.  The LEXCOR panel was blinded to the response classification and tumor measurements of the site and the sponsor.  All measurable lesions were identified and then measured bidimensionally with calipers.  The sum of the products of the greatest perpendicular diameters (SPD) of all measurable lesions and the percent change from baseline were calculated.  Clinical data and nonmeasurable lesion information were also reviewed, and a response classification was assigned.

Table-1.   Response Classifications

 

CT, computed tomography

SPD, sum of the products of the perpendicular diameters

Single-Agent studies in LG/F NHL Patients

Patients and Methods

     Five Phase II or III single-agent studies in LG/F NHL patients include the following:  a Phase II multidose study, a Phase III multicenter study, a Phase II study in patients with bulky disease (> 10 cm lesions), a Phase II study in patients who responded previously to rituximab therapy, and a Phase II study in which an extended dosing schedule (weekly infusions x 8) was administered.  All patients had relapsed or failed primary therapy.  Patients with lesions > 10 cm were excluded in all but the bulky disease study.  Prior rituximab therapy was allowed only in the rituximab retreatment study.  Patients received 375 mg/m² of rituximab once weekly times four during the multidose study, the pivotal trial, the bulky disease study, and the rituximab retreatment study.  Patients in the extended dosing study received 375 mg/m² of rituximab once weekly times eight.

Safety

     Most patients in the single-agent studies experienced an adverse event (AE).  Most AEs were infusion-related, occurred within the first few hours of infusion, and resolved with interruption of the infusion, medication, or no treatment.  The majority of AEs were Grade 1 or 2 and the frequency of AEs decreased with subsequent infusions.  The most common adverse events during the treatment period included fever, chills, asthenia, nausea, headache, and pruritus, while the most common adverse events reported during follow up included neutropenia, leukopenia, sinusitis, fever, peripheral edema, and hyperglycemia.  Grade 3 or 4 events included leukopenia, neutropenia, thrombocytopenia, anemia, bronchospasm, dyspnea, hypotension, chills, and hyperglycemia.  Serious infections (Grade 3 or 4) were rare in the single-agent studies.  In the Phase II or III single-agent studies, 1 of 331 patients (< 1% of patients) developed a detectable human antichimeric antibody (HACA) response following treatment.

Efficacy

     The overall response rates (ORRs) ranged from 40% to 60% in evaluable patients.  Patients with bulky disease (lesions > 10 cm), which is considered to be an indicator of poor response, had an ORR of 43%.  Patients who had responded previously to rituximab therapy responded to retreatment (40% ORR).  Increasing the number of infusions to eight from four provided an increased ORR (60% vs. 50%).  Response rates for evaluable patients in the single‑agent studies are presented in Fig. (3).

Fig. (3).  Response rates in evaluable patients.

     For the evaluable patients in the Phase III multicenter study, the median duration of response (DR) for evaluable patients was 11.6 months and the median time to progression (TTP) was 13.2 months.  The median DR and TTP have not been reached for the extended dosing study or the retreatment study; therefore, Kaplan-Meier estimates were calculated.  The Kaplan-Meier estimate of median DR was 13.4+ months for patients who received an extended dosage and 16.3+ months for patients retreated with rituximab.  The Kaplan-Meier estimate of median TTP was 19.4+ months in the extended dosing study and 17.8+ months in the retreatment study.  Median DR and TTP for evaluable patients are presented in Fig. (4).

Fig. (4). Median DR and TTP for rituximab responders. *Indicates the median DR and TTP have not been reached and Kaplan-Meier estimates are presented.

     Extending the dosing schedule to eight weeks from four weeks improved the pharmacokinetic profile.  In the extended dosing study, the mean postinfusion serum concentration of rituximab increased with each infusion from the first (246 mg/mL) through the eighth infusion (550 mg/mL).  For the first four infusions, the mean postinfusion serum concentration of rituximab was similar between patients in the extended dosing study and a comparison group of patients who received four infusions. Mean preinfusion concentrations remained above 200 mg/mL for the fifth through the eighth infusion.

Combination Studies in LG/F NHL Patients

Patients and Methods

     Three Phase II combination studies include the combination of rituximab with CHOP chemotherapy [28], rituximab with interferon alfa-2a [29], and rituximab with IDEC‑Y2B8[30, 31].  In all three studies, patients were diagnosed with LG/F NHL; in the IDEC-Y2B8 study, patients could also have intermediate-grade or mantle-cell lymphoma.  All patients were relapsed or refractory except for 31 patients in the CHOP combination study who were naïve to treatment.  Prior rituximab therapy was one of the exclusion criteria.  Patients with lesions > 10 cm were excluded from the CHOP combination study and the interferon alfa-2a combination study.

     In the CHOP combination study, CHOP was administered at standard doses every three weeks for six cycles along with six infusions of rituximab (375 mg/m²).  Two rituximab doses were given both at the beginning and at the end of therapy, and single doses were infused before the third and fifth cycles of CHOP.  In the interferon alfa-2a combination study, rituximab (375 mg/m²) was administered once weekly for four weeks (Weeks 5 to 8) during concurrent treatment (three times a week for twelve weeks) with subcutaneous injections of interferon alfa-2a (5 MIU/injection).  In the IDEC-Y2B8 combination study, IDEC-Y2B8 (0.4 mCi/kg) was injected intravenously following an infusion of rituximab (250 mg/m²).  IDEC-In2B8 (5 mCi), which was used for imaging and dosimetry, was administered after an infusion of rituximab (250 mg/m²) one week before the IDEC‑Y2B8 injection.

Safety

     In the CHOP combination study, the most frequent AEs were attributable to the CHOP therapy rather than to the rituximab therapy, and included hematologic effects, nausea, vomiting, and alopecia.  The most frequent AEs related to rituximab were Grade 1 or 2 and infusion related (i.e., fever, chills, pruritus, and headache).  The most frequent AEs reported in the interferon alfa-2a combination study were related to the interferon alfa-2a therapy and included asthenia, chills, fever, headache, nausea, and myalgia.  In the IDEC‑Y2B8 combination study, toxicity was primarily hematologic, transient, and reversible with no major organ dysfunction.  The most frequent AEs were hematologic effects, chills, fever, and nausea.  In all three studies, the AEs experienced by patients treated with combination therapy were similar to AEs that have been reported for the single agents; no synergistic toxicity was observed from the combination of therapies.  Additionally, HACA was not detected in any patient treated in a combination study.

Efficacy

     The ORRs ranged from 45% to 100% in evaluable patients.  All 38 evaluable patients responded to the rituximab plus CHOP combination therapy (100% ORR).  Rituximab combined with interferon alfa-2a produced an ORR of 45% and rituximab combined with IDEC-Y2B8 produced an ORR of 65%.  Response rates for evaluable patients in the combination studies are presented in Fig. (3).

     Mean DR and TTP for evaluable patients have not been reached for the combination studies; therefore, Kaplan-Meier estimates were calculated.  The median DR is estimated at 39.1+ months in the CHOP combination study, 20.3+ months in the interferon alfa-2a combination study, and 11.7+ months in the IDEC‑Y2B8 combination study.  The median TTP is estimated at 40.5+ months in the CHOP combination study, 23.2+ months in the interferon alfa-2a combination study, and 12.9+ months in the IDEC-Y2B8 combination study.  Kaplan-Meier estimates of median DR and TTP for evaluable patients are presented in Fig. (4).

Future Clinical Development

     After the approval of rituximab, IDEC and Genentech have continued to expand and explore the clinical application and therapeutic potential of rituximab in various oncologic diseases.  Several programs have been initiated for this purpose including a research agreement with the National Cancer Institute (NCI).  Additionally, research concepts have been approved for several Investigator Sponsored Trials. Through these programs, studies will be conducted to evaluate the safety and efficacy of rituximab in the following areas:  HIV‑related lymphoma, chronic lymphocytic lymphoma, acute lymphocytic lymphoma, mantle-cell lymphoma, multiple myeloma, autologous bone marrow transp-lantation, and post-transplant lymphoproliferative disease.  Similar programs have also been initiated by F. Hoffmann-La Roche Ltd. for the continued development of rituximab in the European Union.

     Currently, we are conducting a Phase II study of the safety and efficacy of rituximab in combination with CHOP chemotherapy in 35 previously untreated patients with intermediate- or high-grade NHL.  A Phase III study of this combination therapy versus CHOP alone will be initiated early in 2000.  Additionally, a Phase II study of the safety and efficacy of rituximab in combination with G-CSF in NHL patients is being conducted in the Netherlands.

     In addition to the clinical development of rituximab in expanded indications, future avenues of exploration include methods to improve its efficacy.  Areas of investigation may include the combination of rituximab with other agents such as cytokines, IL-2, GM‑CSF, or interferon (IFN) to upregulate CD20 expression, and the use of rituximab to augment effector cell functions.

Summary

     Rituximab, given as a 375 mg/m² infusion once weekly time four, is safe and has significant clinical activity in patients with relapsed or refractory LG/F NHL.  Rituximab is well tolerated and does not impair marrow reserves; thus, subsequent chemotherapy is not precluded.  Outpatient therapy is feasible and a full course of treatment is completed in 22 days.  Since its approval in November 1997, rituximab has become the standard treatment for relapsed or refractory LG/F NHL (IWF: A – D).

     Additionally, rituximab is safe and well tolerated and has significant clinical activity in patients with bulky relapsed or refractory LG/F NHL, and in patients who were treated previously with rituximab.  Retreatment is not limited by HACA production, defers toxic alternative treatments, and preserves marrow function.  The dosing schedule can be increased to eight infusions once weekly with similar safety and efficacy as the approved dosing schedule, while improving the pharmacokinetic profile.

     Combining rituximab with CHOP chemotherapy and with radiotherapy (IDEC‑Y2B8) provides greater efficacy than rituximab alone.  Improved efficacy rates do not compromise safety; significant additional toxicity is not observed with combination therapy.

Abbreviations

ADCC        =     Antibody-dependent cellular cytotoxicity

AE              =     Adverse event

CDC           =     Complement-dependent cytotoxicity

CHO          =     Chinese hamster ovary

CLL           =     Chronic lymphocytic lymphoma

DR             =     Duration of response

FDA           =     US Food an Drug Administration

HACA        =     Human antichimeric antibody

HD             =     Hodgkin’s disease

IFN            =     Interferon

LEXCOR   =     Lymphoma Expert’s Confirmation of Response

LG/F          =     Low-grade or follicular

NCI            =     National Cancer Institute

NHL           =     Non-Hodgkin’s lymphoma

ORR          =     Overall response rate

SPD            =     Sum of the products of the greatest perpendicular diameters

TTP            =     Time to progression

References

[1]            Reff, M.; Carner, K.; Chambers, K.; Chinn, P.; Leonard, J.; Raab, R.; Newman, R.; Hanna, N. and Anderson, D.  (1994)  Blood, 83(2), 435-445.

[2]            Stashenko, P.; Nadler, L.; Hardy, R. and Schlossman, S.  (1980)  J. Immunol., 125(4), 1678-1685.

[3]            Demidem, A.; Lam, T.; Alas, S.; Hariharan, K.; Hanna, N. and Bonavida, B.  (1997)  Cancer Biother. and Radiopharm, 12(3), 177-185.

[4]            Maloney, D.; Smith, B. and Appelbaum, F.  (1996)  Blood, 88(10), 637a.

[5]            Anderson, K.; Bates, M.; Slaughenhoupt, B.; Pinkus, G.; Schlossman, S. and Nadler, L.  (1984)  Blood, 63(6), 1424-1433.

[6]            Tedder, T.; Boyd, A.; Freedman, A.; Nadler, L. and Schlossman, S.  (1985) Immunol., 135(2), 973-979.

[7]            Tedder, T.; Forsgren, A.; Boyd, A.; Nadler, L. and Schlossman, S.  (1986)  Eur. J. Immunol., 16, 881-887.

[8]            Golay, J.; Clark, E. and Beverley, P.  (1985) J. Immunol., 135(6), 3795-3801.

[9]            Clark, E.; Shu, G. and Ledbetter, J.  (1985)  Proc. Natl. Acad. Sci., USA, 82(March), 1766-1770.

[10]        Tedder, T.; Zhou, L.; Bell, P.; Frizzel, R. and Bubien, J.  (1990)  Cell Biochem, 140, 195.

[11]        Freedman, A.; Pedrazzini, A. and Nadler, L.  (1991)  Cancer. Invest., 9(1), 69‑84.

[12]        Longo, D.; DeVita Jr., V.; Jaffe, E.; Mauch, P. and Urba, W.  (1993) in Cancer:  Principles & Practice of Oncology  (DeVita Jr. VT, Hellman S and Rosenberg SA, Eds.), J.B. Lippincott Co., Philadelphia, pp. 1859-1918.

[13]        Einfeld, D.; Brown, J.; Valentine, M.; Clark, E. and Ledbetter, J.  (1988)  EMBO J., 7(3), 711-717.

[14]        Press, O.; Appelbaum, F.; Ledbetter, J.; Martin, P.; Zarling, J.; Kidd, P. and Thomas, E.  (1987)  Blood, 69(2), 584-591.

[15]        LoBuglio, A.; Wheeler, R.; Trang, J.; Haynes, A.; Rogers, K.; Harvey, E.; Sun, L.; Ghrayeb, J. and Khazaeli, M.  (1989)  Proc. Natl. Acad. Sci., USA, 86, 4220-4224.

[16]        Hosono, M.; Endo, K.; Sakahara, H.; Watanabe, Y.; Saga, T.; Nakai, T.; Kawai, C.; Matsumori, A.; Yamada, T.; Watanabe, T. and Konishi, J.  (1992)  Br. J. Cancer, 65, 197-200.

[17]        Meredith, R.; Khazaeli, M.; Plott, W.; Brezovich, I.; Russell, C.; Wheeler, R.; Spencer, S. and LoBuglio, A.  (1992)  Antibody, Immunoconjugates, and Radiopharmaceuticals, 5(1), 75-80.

[18]        Khazaeli, M.; Saleh, M.; Liu, T.; Meredith, R.; Wheeler, R.; Baker, T.; King, D.; Secher, D.; Allen, L.; Rogers, K.; Colcher, D.; Schlom, J.; Shochat, D. and LoBuglio, A.  (1991)  Cancer Res., 51, 5461-5466.

[19]        World Health Organization  (1979) WHO Handbook for Reporting Results of Cancer Treatment, Report Nbr.: 48, 5-41.

[20]        Cheson, B.; Bennett, J.; Grever, M.; Kay, N.; Keating, M.; O'Brien, S. and Rai, K.  (1996)  Blood, 87(12), 4990-4997.

[21]        Lister, T.; Crowther, D.; Sutcliffe, S.; Glatstein, E.; Canellos, G.; Young, R.; Rosenberg, S.; Coltman, C. and Tubiana, M.  (1989) J. Clin. Oncol., 7(11), 1630‑1636.

[22]        Cheson, B.; Cassileth, P.; Head, D.; Schiffer, C.; Bennett, J.; Bloomfield, C.; Brunning, R.; Gale, R.; Grever, M.; Keating, M.; Sawitsky, A.; Stass, S.; Weinstein, H. and Woods, W.  (1990) J. Clin. Oncol., 8(5), 813-819.

[23]        Oken, M.; Creech, R.; Tormey, D.; Horton, J.; Davis, T.; McFadden, E. and Carbone, P.  (1982)  Am.  J. Clin. Oncol., 5, 649-655.

[24]        Horning, S.; Cheson, B.; Peterson, B.; Grillo-López, A.; Carter, W.; Varns, C.; Klippenstein, D.; Kossman, K.; Kortman, K.; Rosen, P.; Morrison, V.; Just, R.; Parker, E. and Dallaire, B.  (1997)  Proc. Am. Soc. Clin. Oncol., 16(May), 18a.

[25]        Grillo-López, A.; Horning, S.; Cheson, B.; Peterson, B.; Coiffier, B.; Hagenbeek, A.; Hiddemann, W.; Marcus, R. and Lister, T.  (1997)  Exp. Hematol., 25(8), 732.

[26]        McLaughlin, P.; Grillo-López, A.; Link, B.; Levy, R.; Czuczman, M.; Williams, M.; Heyman, M.; Bence-Bruckler, I.; White, C.; Cabanillas, F.; Jain, V.; Ho, A.; Lister, J.; Wey, K.; Shen, D. and Dallaire, B.  (1998) J. Clin. Oncol., 16(8), 2825-2833.

[27]        Grillo-López, A.; McLaughlin, P.; Cheson, B.; Czuczman, M.; Maloney, D.; Horning, S.; Link, B.; Davis, T.; Cabanillas, F. and White, C.  (1999)  Proc. of ASCO, 18, 13A.

[28]        Czuczman, M.; Grillo-López, A.; White, C.; Saleh, M.; Gordon, L.; LoBuglio, F.; Jonas, C.; Klippenstein, D.; Dallaire, B. and Varns, C.  (1999) J. Clin. Oncol., 17(1), 268-276.

[29]        Davis, T.; Maloney, D.; White, C.; Grillo-López, A.; Williams, M.; Weiner, G.; Sklenar, T. and Levy, R.  (1998)  Proc. Am. Soc. Clin. Oncol., 17(May), 11a.

[30]        Knox, S.; Goris, M.; Trisler, K.; Negrin, R.; Davis, T.; Liles, T.-M.; Grillo‑López, A.; Chinn, P.; Varns, C.; Ning, S.-C.; Fowler, S.; Deb, N.; Becker, M.; Marquez, C. and Levy, R.  (1996)  Clin. Cancer. Res., 2, 457-470.

[31]        Witzig, T.E.; White, C.A.; Wiseman, G.A.; Gordon, L.I.; Emmanouilides, C.; Raubitschek, A.; Janakiraman, N.; Gutheil, J.; Schilder, R.J.; Spies, S.; Silverman, D.H.; Parker, E. and Grillo-López, A.  (1999) J. Clin. Oncol., 17(12), 3793-3803.