Current Clinical Trials of Molecularly Targeted Agents in Children With Cancer, Part 2

April 1, 2002

A number of molecularly targeted agents directed at critical cell survival and cell proliferation pathways have recently entered clinical evaluation in children with cancer. These agents offer the potential for more effective anticancer therapy while simultaneously diminishing acute and long-term toxic effects. Systematic evaluations of targeted agents are essential to achieving continued improvements in outcome for children with cancer. Brief summaries of the rationale for conducting studies of several agents in children are provided below. Following these summaries is a listing of phase I, phase I/II, phase II, and pilot studies of these and other agents in pediatric populations.

A number of molecularly targeted agents directed atcritical cell survival and cell proliferation pathways have recently enteredclinical evaluation in children with cancer. These agents offer the potentialfor more effective anticancer therapy while simultaneously diminishing acute andlong-term toxic effects. Systematic evaluations of targeted agents are essentialto achieving continued improvements in outcome for children with cancer. Briefsummaries of the rationale for conducting studies of several agents in childrenare provided below. Following these summaries is a listing of phase I, phaseI/II, phase II, and pilot studies of these and other agents in pediatricpopulations.

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource, a continuation of the article begun in the previous issue, is devoted to current clinical trials of molecularly targeted agents for children with cancer.

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, online access is available at, or contact the Cancer Information Service offices (1-800-4-CANCER).


G3139 (bcl-2 antisense, Genasense) is an 18-mer phosphorothioateoligonucleotide antisense molecule that binds to the first six codons of humanbcl-2 mRNA and reduces expression of the bcl-2 gene by preventing translationand production of the encoded protein.[1] By reducing levels of bcl-2 protein,G3139 increases the activation of the apoptotic pathway in response to variousstimuli such as chemotherapy, irradiation, or other DNA-damaging events. Tumorxenograft models have demonstrated single-agent activity of G3139 againstfollicular lymphoma cell lines[1] and against a neuroendocrine malignancy (ie,Merkel cell carcinoma).[2] In xenograft models in which G3139 was tested incombination with chemotherapy, enhanced antitumor activity was observed forcyclophosphamide (Cytoxan, Neosar) against non-Hodgkin lymphoma,[3] fordacarabazine (DTIC-Dome) against melanoma,[4] and for cisplatin against gastriccarcinoma.[5]

G3139 has been studied in adults with cancer, both as a single agent[6] andin combination with chemotherapy.[7,8] Because antisense-mediateddown-regulation of bcl-2 levels requires several days, G3139 is administeredintravenously as a single agent for 4 to 7 days prior to the initiation ofchemotherapy.

G3139 has been generally well tolerated, and serum levels in excess of thoseassociated with bcl-2 down-regulation and potentiation of chemotherapy have beenachieved. Combinations of G3139 with chemotherapy have not produced substantialincreases in toxicity compared to those expected for chemotherapy alone.Down-regulation of bcl-2 in peripheral blood mononuclear cells and in tumorcells has been observed in adult studies.[6,8]

G3139 may eventually have utility against several pediatric cancers in whichbcl-2 may be associated with treatment resistance, includingneuroblastoma,[9,10] synovial sarcoma,[11,12] acute lymphoblasticleukemia,[13,14] and acute myeloid leukemia.[15,16] G3139 is being evaluated incombination with doxorubicin and cyclophosphamide in a pediatric solid tumorphase I study (ADVL0211) that should begin enrollment in the first quarter of2002.


ZD1839 (Iressa) is an orally available agent that selectively inhibits thetyrosine kinase activity of the epidermal growth factor receptor (EGFr).[17]ZD1839 inhibits ligand-induced EGFr autophosphorylation, leading generally to acytostatic effect.[17] In preclinical models, oral dosing occasionally causestumor regression but more generally causes growth inhibition of EGFr-expressingtumor xenografts.[18,19] The antitumor activity of a variety of conventionalchemotherapeutic agents can be potentiated when combined with ZD1839.[18,19]

Phase I trials of ZD1839 demonstrated that the agent is well tolerated atdoses that suppress EGFr phosphorylation in surrogate tissues.[20] When ZD1839is administered daily, the most common toxicities observed are grade 1/2diarrhea and a distinctive acneiform skin rash.[17] The pharmacokinetics ofZD1839 justify administration on a once-daily schedule. ZD1839 has inducedresponses in patients with colorectal, ovarian, non-small-cell lung cancer,head and neck, renal, and hormone-resistant prostate cancers.[17,21,22] It hasbeen safely combined with several conventional chemotherapy agents, includingcisplatin/gemcitabine (Gemzar)[23] and fluorouracil/leucovorin.[24] Another EGFrinhibitor, cetuximab (IMC-C225, Erbitux) has been safely administered incombination with cisplatin,[25,26] irinotecan (CPT-11, Camptosar),[27] andradiation therapy,[28] further supporting the feasibility of combining thisclass of agent with conventional anticancer treatments.

The expression of EGFr in neuroblastoma,[29,30] rhabdomyosarcoma,[29,31]osteosarcoma,[32] and glioma[33] provides the rationale for studying ZD1839 inchildren. A pediatric phase I trial of ZD1839 (ADVL0016) in children with solidtumors is scheduled to begin in the first quarter of 2002. For children withhigh-grade gliomas (either supratentorial or brainstem), the Pediatric BrainTumor Consortium is conducting a phase I study of ZD1839 in combination withradiation therapy (PBTC-007).


Rituximab (Rituxan) is a mouse/human chimeric antibody that targets the CD20antigen, which is present exclusively on B cells (pre-B and mature Blymphocytes) and on most B-cell lymphomas.[34,35] Rituximab kills cells viaseveral mechanisms, including antibody-dependent cellular toxicity, activationof the complement cascade,[36,37] and modulation of signaling pathways leadingto apoptosis.[38,39] In preclinical models, rituximab enhances the activity ofchemotherapy agents.[40-43]

Rituximab was first shown to be active against low-grade or follicularnon-Hodgkin lymphoma[44] and was subsequently found to be active against diffuselarge-cell lymphoma.[45] Toxicities attributed to rituximab are generally mildand most often associated with the first infusion. An acute tumor lysissyndrome, likely related to cytokine release, has occurred in patients with highcirculating lymphocyte count or large tumor burden.[46-48] Rituximab has beensafely combined with standard CHOP chemotherapy (cyclophosphamide, doxorubicinHCl, vincristine [Oncovin], prednisone),[49,50] with no substantial increase intoxicity above that associated with the CHOP regimen alone.

A randomized trial in elderly adults with diffuse large-cell lymphomacomparing CHOP to CHOP plus rituximab demonstrated significantly higherevent-free survival and survival rates in patients receiving rituximab pluschemotherapy.[51] Rituximab has also be been safely combined with an intensivechemotherapy regimen used to treat Burkitt lymphoma.[52]

Among the lymphomas that occur in children, diffuse large-cell lymphoma andBurkitt lymphoma both express high levels of CD20.[53-57] Rituximab inducesapoptosis in Burkitt lymphoma cell lines,[38,39] and anti-CD20 monoclonalantibodies are active in a Burkitt lymphoma xenograft model.[58] There areanecdotal reports of children with recurrent Burkitt lymphoma[59] and childrenwith post-transplant lymphoproliferative disease responding to rituximab.[60]

A Children’s Oncology Group pilot study (ANHL01P1) combining rituximab withstandard chemotherapy agents in children with newly diagnosed Burkitt lymphomaand diffuse large-cell lymphoma should begin accrual in the second quarter of2002. A second Children’s Oncology Group study (ANHL0121) will combinerituximab with ICE (ifosfamide [Ifex], carboplatin [Paraplatin], etoposide) inchildren with recurrent Burkitt lymphoma and diffuse large-cell lymphoma.Rituximab plus ICE chemotherapy has shown substantial activity in adults withrecurrent high-grade B-cell lymphomas.[61] The ANHL0121 study should open in thethird quarter of 2002.


Yttrium-90-ibritumomab tiuxetan (IDEC-Y2B8, 90Y-Zevalin) is also to bestudied in children with recurrent B-cell lymphomas. Ibritumomab is a murineIgG1 kappa immunoglobulin that, like rituximab, reacts with the CD20 antigen. Itis covalently attached to the chelator tiuxetan, which can then secure eitherthe pure beta emitter yttrium-90 for therapeutic applications or secureindium-111 for imaging/dosimetry.[62]

A randomized trial in adults with relapsed or refractory low-grade,follicular, or CD20+ transformed B-cell non-Hodgkin lymphoma compared weeklyrituximab (four doses) to a regimen in which a single dose of IDEC-Y2B8 waspreceded by two doses of rituximab to clear peripheral B-cells and improvebiodistribution of IDEC-Y2B8.[62] Patients receiving IDEC-Y2B8 had a higherresponse rate compared to those receiving rituximab alone.[63] A pediatric phaseI study of IDEC-Y2B8 (ADVL0013) in children with recurrent B-cell lymphomasshould begin accruing patients in the third quarter of 2002.

In Summary

The clinical trials of the molecularly targeted agents described above andthose described in last month’s issue of Oncology represent necessary earlysteps towards rationalizing therapy for children with cancer. Realizing thepotential benefits of targeted therapies will require increased understanding ofthe biology of pediatric cancers, as well as systematic clinical evaluations oftargeted agents. Eventual success will require the concerted efforts ofmolecular biologists elucidating key survival and cell death pathways inspecific childhood cancers, of preclinical researchers using animal models toprioritize new agents for evaluation in children, and of clinicians implementingwell-conceived development plans for those agents selected for study inchildren.

Phase II

Title: A Phase II Study of Ifosfamide, Carboplatin, Etoposide, andRituximab as Retrieval Therapy for Relapsed/Refractory NHL—A COG Study
Protocol Number: ANHL0121
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116

Phase I/II

Title: A Phase I/II Trial of ZD1839 (Iressa) and Radiation in PediatricPatients Newly Diagnosed With Brain Stem Tumors or Incompletely ResectedSupratentorial Malignant Gliomas With Phase II Limited to Brain Stem Tumors
Protocol Number: PBTC-007
Participating Institutions: Pediatric Brain Tumor Consortium
Contact: J. Russell Geyer, (206) 526-2106

Phase I

Title: Phase I Study of Rituximab Followed By Yttrium Y 90Ibritumomab Tiuxetan With or Without Autologous Peripheral Blood Stem CellTransplantation in Children With Recurrent or Refractory CD20-Positive Lymphoma
Protocol Number: COG-ADVL0013
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116
Latest Information:

Title: A Phase I Study of ZD1839 (Iressa), an Oral Epidermal GrowthFactor Receptor Tyrosine Kinase Inhibitor, in Children With Refractory SolidTumors
Protocol Number: ADVL0016
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116

Title: A Phase I Trial of BCL-2 Antisense Combined With CytotoxicChemotherapy in Relapsed Childhood Solid Tumors
Protocol Number: ADVL0211
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116

Pilot Studies

Title: A Pilot Study to Determine the Toxicity of the Addition ofRituximab to the Induction and Consolidation Phases and the Addition ofRasburicase to the Reduction Phase in Children With Newly Diagnosed AdvancedB-Cell Leukemia/Lymphoma Treated with LMB/FAB Therapy
Protocol Number: ANHL01P1
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116

Other Agents of Interest in Clinical Trials

Title: Phase II Study of Gemcitabine in Children With Relapsed orRefractory AcuteLymphoblastic Leukemia or Acute Myelogenous Leukemia
Protocol Number: CCG-A0999, COG-ADVL0022
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:

Title: Phase II Study of Compound 506U78 in Patients with RefractoryT-Cell Malignancies
Protocol Number: CCG-P9673, POG-9673
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:

Title: Phase II Study of Rebeccamycin Analogue in Children WithSolid Tumors or Non-Hodgkin's Lymphoma
Protocol Number: COG-P9963
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:

Title: Phase I Study of Flavopiridol in Children With Relapsed orRefractory Solid Tumors or Lymphomas
Protocol Number: CCG-AO972, COG-ADVL0017, NCI-A0972
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:

Title: Phase I Study of hu14.18-Interleukin-2 Fusion Protein inChildren With Refractory or Recurrent Neuroblastoma or Other GD2-Positive Tumors
Protocol Number: ADVL0018
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:

Title: Phase II Pilot Study of Modified MultiagentBerlin-Frankfurt-Muenster-86 Chemotherapy With or Without 506U78 in PatientsWith Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia
Protocol Number: COG-AALL00P2
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:


1. Cotter FE, Johnson P, Hall P, et al: Antisense oligonucleotides suppressB-cell lymphoma growth in a SCID-hu mouse model. Oncogene 9:3049-3055, 1994.

2. Schlagbauer-Wadl H, Klosner G, Heere-Ress E, et al: Bcl-2 antisenseoligonucleotides (G3139) inhibit Merkel cell carcinoma growth in SCID mice. JInvest Dermatol 114:725-730, 2000.

3. Klasa, RJ, Bally MB, Ng R, et al: Eradication of human non-Hodgkin’slymphoma in SCID mice by bcl-2 antisense oligonucleotides combined with low-dosecyclophosphamide. Clin Cancer Res 6:2492-2500, 2000.

4. Jansen B, Schlagbauer-Wadl H, Brown BD, et al: Bcl-2 antisense therapychemosensitizes human melanoma in SCID mice. Nat Med 4:232-234, 1998.

5. Wacheck V, Heere-Ress E, Halaschek-Wiener J, et al: Bcl-2 antisenseoligonucleotides chemosensitize human gastric cancer in a SCID mousexenotransplantation model. J Mol Med 79:587-593, 2001.

6. Waters JS, Webb A, Cunningham D, et al: Phase I clinical andpharmacokinetic study of Bcl-2 antisense oligonucleotide therapy in patientswith non-Hodgkin’s lymphoma. J Clin Oncol 18:1812-1823, 2000 (see comments).

7. Chi KN, Gleave ME, Klasa R, et al: A phase I dose-finding study ofcombined treatment with an antisense bcl-2 oligonucleotide (Genasense) andmitoxantrone in patients with metastatic hormone-refractory prostate cancer.Clin Cancer Res 7:3920-3927, 2001.

8. Jansen B, Wacheck V, Heere-Ress E, et al: Chemosensitisation of malignantmelanoma by bcl-2 antisense therapy. Lancet 356:1728-1733, 2000.

9. Krajewski S, Chatten J, Hanada M, et al: Immunohistochemical analysis ofthe bcl-2 oncoprotein in human neuroblastomas. Comparisons with tumor celldifferentiation and N-Myc protein. Lab Invest 72:42-54, 1995.

10. Castle VP, Heidelberger KP, Bromberg J, et al: Expression of theapoptosis-suppressing protein bcl-2, in neuroblastoma is associated withunfavorable histology and N-myc amplification. Am J Pathol 143:1543-1550, 1993.

11. Suster S, Fisher C, Moran CA: Expression of bcl-2 oncoprotein in benignand malignant spindle cell tumors of soft tissue, skin, serosal surfaces, andgastrointestinal tract. Am J Surg Pathol 22:863-872, 1998.

12. Mancuso T, Mezzelani A, Riva C, et al: Analysis of SYT-SSX fusiontranscripts and bcl-2 expression and phosphorylation status in synovial sarcoma.Lab Invest 80:805-813, 2000.

13. Coustan-Smith E, Kitanaka A, Pui CH, et al: Clinical relevance of bcl-2overexpression in childhood acute lymphoblastic leukemia. Blood 87:1140-1146,1996.

14. Liu T, Bruggers CS, Moos PJ, et al: Changes in protein expression ofbcl-2 family members following treatment in childhood leukemia. Blood 94(suppl1):81a, 1999.

15. Karakas T, Maurer U, Weidmann E, et al: High expression of bcl-2 mRNA asa determinant of poor prognosis in acute myeloid leukemia. Ann Oncol 9:159-165,1998 (see comments).

16. Filipits M, Stranzl T, Pohl G, et al: Drug resistance factors in acutemyeloid leukemia: a comparative analysis. Leukemia 14:68-76, 2000.

17. Ciardiello F, Tortora G: A novel approach in the treatment of cancer:targeting the epidermal growth factor receptor. Clin Cancer Res 7:2958-2970,2001.

18. Sirotnak FM, Zakowski MF, Miller VA, et al: Efficacy of cytotoxic agentsagainst human tumor xenografts is markedly enhanced by coadministration ofZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res6:4885-4892, 2000.

19. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect andpotentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa),an epidermal growth factor receptor-selective tyrosine kinase inhibitor. ClinCancer Res 6:2053-2063, 2000.

20. Albanell J, Rojo F, Averbuch S, et al: Pharmacodynamic studies of theepidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients:Histopathologic and molecular consequences of receptor inhibition. J Clin Oncol20:110-124, 2002.

21. Baselga J, Yano S, Giaccone G, et al: Initial results from a phase IItrial of ZD1839 (Iressa) as second- or third-line monotherapy for patients withadvanced non-small-cell lung cancer (IDEAL 1) (abstract). Clin Cancer Res7:630A, 2001.

22. Ferry D, Hammond L, Ranson M., et al: Intermittent oral ZD1839 (Iressa),a novel epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI),shows evidence of good tolerability and activity: Final results from a phase Istudy)(abstract). Proc Am Soc Clin Oncol 19:3a, 2000.

23. Giaccone G, Gonzalez Larriba JL, Smit EF, et al: Combination therapy withZD1839 (‘Iressa’), an orally active, selective, epidermal growth factorreceptor tyrosine kinase inhibitor (EGFR-TKI), gemcitabine and cisplatin, inpatients with advanced solid tumours: Promising preliminary results ontolerability, efficacy and pharmacokinetics. Clin Cancer Res 7(suppl):3765s,2001.

24. Hammond LA, Figueroa J, Schwartzberg L, et al: ZD1839 (‘Iressa’), anepidermal growth factory receptor tyrosine kinase inhibitor (EGFR-TKI), incombination with 5-fluorouracil (5-FU) and leucovorin (LV), in patients withadvanced colorectal cancer (aCRC). Clin Cancer Res 7(suppl):3764s, 2001.

25. Shin DM, Donato NJ, Perez-Soler R, et al: Epidermal growth factorreceptor-targeted therapy with C225 and cisplatin in patients with head and neckcancer. Clin Cancer Res 7:1204-1213, 2001.

26. Baselga J, Pfister D, Cooper MR, et al: Phase I studies of anti-epidermalgrowth factor receptor chimeric antibody C225 alone and in combination withcisplatin. J Clin Oncol 18:904-914, 2000.

27. Saltz L, Rubin MS, Hochster HS, et al: Acne-like rash predicts responsein patients treated with cetuximab (IMC-C225) plus irinotecan (CPT-11) in CPT-11-refractorycolorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR).Clin Cancer Res 7(suppl):3765s, 2002.

28. Robert F, Ezekiel MP, Spencer SA, et al: Phase I study of anti-epidermalgrowth factor receptor antibody cetuximab in combination with radiation therapyin patients with advanced head and neck cancer. J Clin Oncol 19:3234-3243, 2001.

29. Houghton PJ, Harwood FC, Sharif M: Epidermal growth factor activation ofERK1/2 in pediatric cancer cell lines and sensitivity to the selective EGFR-tyrosinekinase inhibitor ZD1839 (‘Iressa’). Proc Am Assoc Cancer Res 41:481-482,2000.

30. Meyers MB, Shen WP, Spengler BA, et al: Increased epidermal growth factorreceptor in multidrug-resistant human neuroblastoma cells. J Cell Biochem38:87-97, 1988.

31. De Giovanni C, Landuzzi L, Frabetti F, et al: Antisense epidermal growthfactor receptor transfection impairs the proliferative ability of humanrhabdomyosarcoma cells. Cancer Res 56:3898-3901, 1996.

32. Oda Y, Wehrmann B, Radig K, et al: Expression of growth factors and theirreceptors in human osteosarcomas. Immunohistochemical detection of epidermalgrowth factor, platelet-derived growth factor and their receptors: itscorrelation with proliferating activities and p53 expression. Gen Diagn Pathol141:97-103, 1995.

33. Bredel M, Pollack IF, Hamilton RL, et al: Epidermal growth factorreceptor expression and gene amplification in high-grade non-brainstem gliomasof childhood. Clin Cancer Res 5:1786-1792, 1999.

34. Stashenko P, Nadler LM, Hardy R, et al: Characterization of a human Blymphocyte-specific antigen. J Immunol 125:1678-1685, 1980.

35. Nadler LM, Ritz J, Hardy R, et al: A unique cell surface antigenidentifying lymphoid malignancies of B cell origin. J Clin Invest 67:134-40,1981.

36. Harjunpaa A, Junnikkala S, Meri S: Rituximab (anti-CD20) therapy ofB-cell lymphomas: Direct complement killing is superior to cellular effectormechanisms. Scand J Immunol 51:634-641, 2000.

37. Bellosillo B, Villamor N, Lopez-Guillermo A, et al: Complement-mediatedcell death induced by rituximab in B-cell lymphoproliferative disorders ismediated in vitro by a caspase- independent mechanism involving the generationof reactive oxygen species. Blood 98:2771-2777, 2001.

38. Hofmeister JK, Cooney D, Coggeshall KM: Clustered CD20 induced apoptosis:src-family kinase, the proximal regulator of tyrosine phosphorylation, calciuminflux, and caspase 3-dependent apoptosis. Blood Cells Mol Dis 26:133-143, 2000.

39. Mathas S, Rickers A, Bommert K, et al: Anti-CD20- and B-cellreceptor-mediated apoptosis: Evidence for shared intracellular signalingpathways. Cancer Res 60:7170-7176, 2000.

40. Demidem A, Lam T, Alas S, et al: Chimeric anti-CD20 (IDEC-C2B8)monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing bycytotoxic drugs. Cancer Biother Radiopharm 12:177-186, 1997.

41. Alas S, Bonavida B: Rituximab inactivates signal transducer andactivation of transcription 3 (STAT3) activity in B-non-Hodgkin’s lymphomathrough inhibition of the interleukin 10 autocrine/paracrine loop and results indown- regulation of bcl-2 and sensitization to cytotoxic drugs. Cancer Res61:5137-5144, 2001.

42. Di Gaetano N, Xiao Y, Erba E, et al: Synergism between fludarabine andrituximab revealed in a follicular lymphoma cell line resistant to the cytotoxicactivity of either drug alone. Br J Haematol 114:800-809, 2001.

43. Chow KU, Sommerlad WD, Boehrer S, et al: Anti-CD20 antibody (IDEC-C2B8,rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes invitro: Role of cytokines, complement, and caspases. Haematologica 87:33-43,2002.

44. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimericanti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half ofpatients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833,1998.

45. Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonalantibody) for the treatment of patients with relapsing or refractory aggressivelymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998.

46. Byrd JC, Waselenko JK, Maneatis TJ, et al: Rituximab therapy inhematologic malignancy patients with circulating blood tumor cells: Associationwith increased infusion-related side effects and rapid blood tumor clearance. JClin Oncol 17:791-795, 1999.

47. Jensen M, Winkler U, Manzke O, et al: Rapid tumor lysis in a patient withB-cell chronic lymphocytic leukemia and lymphocytosis treated with an anti-CD20monoclonal antibody (IDEC-C2B8, rituximab). Ann Hematol 77:89-91, 1998.

48. Lim LC, Koh LP, Tan P: Fatal cytokine release syndrome with chimericanti-CD20 monoclonal antibody rituximab in a 71-year-old patient with chroniclymphocytic leukemia (letter). J Clin Oncol 17:1962-1963, 1999.

49. Czuczman M, Grillo-Lopez AJ, White CA, et al: Rituximab/CHOPchemoimmunotherapy in patients (pts) with low grade lymphoma (LG/F NHL):Progression free survival (PFS) after 3 years (median) follow-up (abstract 432).Blood 94:99a, 1999.

50. Vose JM, Link BK, Grossbard ML, et al: Phase II study of rituximab incombination with CHOP chemotherapy in patients with previously untreatedintermediate- or high-grade non-Hodgkin’s lymphoma (NHL) (abstract 388). Blood94:89a, 1999.

51. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximabcompared with CHOP alone in elderly patients with diffuse large B-cell lymphoma.N Engl J Med 346:235-242, 2002.

52. Thomas DA, Cortes J, Giles FJ, et al: Rituximab and hyper-CVAD for adultBurkitt’s (BL) or Burkitt’s-like (BLL) leukemia or lymphoma (abstract 3342).Blood 98:804a, 2001.

53. Gregory CD, Tursz T, Edwards CF, et al: Identification of a subset ofnormal B cells with a Burkitt’s lymphoma (BL)-like phenotype. J Immunol139:313-318, 1987.

54. Rosanda C, Cantu-Rajnoldi A, Invernizzi R, et al: B-cell acutelymphoblastic leukemia (B-ALL): a report of 17 pediatric cases. Haematologica77:151-155, 1992.

55. Imamura N, Mtasiwa DM, Ota H, et al: FAB L3 type of B-cell acutelymphoblastic leukemia (B-ALL) without chromosome abnormalities. Am J Hematol35:216-218, 1990.

56. Jennings CD, Foon KA: Recent advances in flow cytometry: Application tothe diagnosis of hematologic malignancy. Blood 90:2863-2892, 1997.

57. Freedman AS: Cell surface antigens in leukemias and lymphomas. CancerInvest 14:252-276, 1996.

58. Buchsbaum DJ, Wahl RL, Normolle DP, et al: Therapy with unlabeled and131I-labeled pan-B-cell monoclonal antibodies in nude mice bearing Raji Burkitt’slymphoma xenografts. Cancer Res 52:6476-6481, 1992.

59. Veerman AJ, Nuijens JH, van der Schoot CE, et al: Rituximab in thetreatment of childhood B-ALL and Burkitt’s lymphoma, report on three cases(abstract 4414). Blood 94:269b, 1999.

60. Faye A, Quartier P, Reguerre Y, et al: Chimaeric anti-CD20 monoclonalantibody (rituximab) in post-transplant B-lymphoproliferative disorder followingstem cell transplantation in children. Br J Haematol 115:112-118, 2001.

61. Kewalramani T, Zelenetz A, Bertino J, et al: Rituximab significantlyincreases the complete response rate in patients with relapsed or primaryrefractory DLBCL receiving ICE as second-line therapy (abstract 1459). Blood98:346a, 2001.

62. Wiseman GA, White CA, Sparks RB, et al: Biodistribution and dosimetryresults from a phase III prospectively randomized controlled trial of Zevalinradioimmunotherapy for low- grade, follicular, or transformed B-cell non-Hodgkin’slymphoma. Crit Rev Oncol Hematol 39:181-194, 2001.

63. Witzig TE, White CA, Gordon LI, et al: Final results of a randomizedcontrolled study of the Zevalin radioimmunotherapy regimen vs a standard courseof rituximab immunotherapy for B-cell NHL (abstract 3591). Blood 96:831a, 2000.