AU2005211669B2 - Treatment of intermediate- and high-grade non-Hodgkins lymphoma with anti-CD20 antibody - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT(S): Biogen Idec, Inc.

ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Nicholson Street Melbourne, 3000.

INVENTION TITLE: "Treatment of intermediate- and high-grade non-Hodgkins lymphoma with antiantibody" The following statement is a full description of this invention, including the best method of performing it known to us: Q'\OPERUEH\2005\Sept\ 2668150 266 doc 23/9/05 18/03 2009 12:41 FAX I0004/0052 0 -2- Treatment f Intermediate- and High-Grade Non-Hodgkins ymphoma with Anti-CD20 Antibody 0This application is a divi onal application of Australian Application No.

67478/00 the specification and awings of which as originally filed are incorporated herein in their entirety by refer e.

SField of the Invention The present invention co cerns methods of treating diffuse large cell lymphoma with anti-CD20 monoclonal anti odies and fragments thereof.

0Backgund of the Invention Non-Hodgki's lympho a is characterized by the malignant growth of B13 lymphocytes. According to the A erican Cancer Society, an estimated 54,000 new cases will be diagnosed, 65% of hich will be classified as intermediate- or high-grade lymphoma. Patients diagnosed intennediate-grade lymphoma have an average survival rate of 2-5 years, and pa ients diagnosed with high-grade lymphoma survive an average of 6 months to 2 years a er diagnosis.

Intermediate- and high-grde lymphomas are much more aggressive at the time of diagnosis than are low-grade I phomas, where patients may survive an average of 5-7 years with conventional theries. Intermediate- and high-grade lymphomas are often characterized by large extraoda bulky tumors and a large number of circulating cancer cells, which often infiltrat. the bone marrow of the patient.

Conventional therapies ha e included chemotherapy and radiation, possibly accompanied by either autologo or allogeneic bone marrow or stem cell transplantation if a suitable dono is available, and if the bone marrow contains too many tumor cells upon harvestin While patients often respond to conventional therapies, they usually relapse wi n several months.

A relatively new approac to treating non-Hodgkin's lymphoma has been to treat patients with a monoclonal atibody directed to a protein on the surface of cancerous B cells. The antibody nay be conjugated to a toxin or radiolabel thereby affecting cell death after binding. Jternatively, an antibody may be engineered with human constant regions such that uman antibody effector mechanisms are generated upon antibody binding which re t in apoptosis or death of the cell.

One antibody currently be g mvestigated for the treatment of intermediate- and high-grade lymphomas is Oncol 3 I-Lym-l)(Techniclone Corp.), which is a murine IgG2a monoclonal antibo which recognizes the HLA-DrlO protein which is N:MelbourneCa s PatennacO00-099o Mp .AU.lSpeci.s~ B222SAU.1 8p on 2009-318.doc l. 3 COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:41 FAX [0005/0052 0 -3- 0 present on the surface of over 8 of lymphoma cells. Only 2% of normal B cells t(noncancerous) express the HL{-Drl 0 molecule. Oncolym® is conjugated to a Iodine- [31(3, a radioactive isotop of iodine which emits ta irraiation for a distance of 00 several millimeters, and is there y thought to be an effective approach to targeting the outer rim of tumors and halting e progression of bulky disease.

However, a potential dis dvantage in using Oncolym® in advanced forms of Snon-Hodgkin's lymphoma is tha such lymphomas are often characterized by bone a marrow involvement. Thus, a stration of a radiolabeled antibody to such patients often results in unwanted myelo uppression and damage to healthy progenitor cells.

'It would be advantageou if alternative therapies and other monoclonal O antibodies could be administere to patients with intermediate- and high-grade lymphomas which circumvent s e of the deficiencies associated with current Ci treatments and decrease the freq ency of relapse.

Smmary of Invention The present invention co cerns the use of anti-CD20 antibodies for the treatment of diffuse large cell lyr phoma. In particular, the present inventors have surprisingly found that Rituximn,, a chimneric anti-CD2 antibody already approved for the treatment of low-grade follicdlar non-Hodgkin's lynphoma is effective to treat diffuse large cell lymphoma in cCnbination with chemotherapy in patients who have relapsed from or are refractory to chemotherapy.

In a first aspect, the invention provides, a method for treating a patient with diffuse large cell lymphoma, conm rising administering to the patient a therapeutically effective amount ofan anti-CD2M antibodyand a chemotherapeutic regimen; hum where m the antibody is a himeric, humanized, or human antibody comprising humanconstant regions, and is nt conjugated to a toxin or radiolabel; and wherein the patient is relapsed from or refractory to chemotherapy In a second aspect, the invntion provides a method for treating a patient with relapsed or refractory diffuse large cell lymphoma, comprising administering to the patient a therapeutically effective Hount of a human anti-CD20 antibody and a chemotherapeutic regimen, where n the antibody is not conjugated to a toxin or In a third aspect, the invenion provides a method for treating a patient with ito ftse larg cellymphoma accompaned by bulky disease, comprising administering t patnt a terapeutically effective amount of unlabeled Rituximab and CHOP In a fourth aspect, the inve tion provides a method for treating a patient with NMelb a oumeaesvaent 0222AU Specis o Sce-3-18.doc o COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:41 FAX Q ]0006/0052 -4relapsed or refractory diffuse laige cell lymphoma, comprising administering to the tpatient a therapeutically effective amount of unlabeled Rituximab and CHOP chemotherapy- 0In a fifth aspect, the invention provides use of an anti-CD20 antibody in the preparation of a medicament for treating a patient with diffuse large cell lymphoma, wherein the antibody is a chimeric, humanized, or human antibody comprising Ohuman constant regions, and is not conjugated to a toxin or radiolabel; Vwherein the patient is relapsed from or refractory to chemotherapy; and _wherein the medicament is for administration of a therapeutically effective amount of the antibody to the patient along with a chemotherapeutic regimen.

oIn a sixth aspect, the invention provides use of a human anti-CD20 antibody in othe preparation of a medicament -for treating a patient with relapsed or refractory diffuse large cell lymphoma, wherein the antibody is not conjugated to a toxin or radiolabel, and the medicament is for administration of a therapeutically effective amount of the antibody to the patient along with a chemotherapy regimen.

In a seventh aspect, the invention provides use of unlabeled Rituximab in the preparation of a medicament for treating a patient with diffuse large cell lymphoma accompanied by bulky disease, wherein the medicament is for administration of a therapeutically effective amount of Rituximab with CHOP chemotherapy.

In an eighth aspect, the invention provides, use of a therapeutically effective amount of unlabeled Rituximab in the preparation of a medicament for treating a patient with relapsed or refractory diffuse large cell lymphoma, wherein the medicament is for administration of a therapeutically effective amount of Rituximab together with CHOP chemotherapy.

Detailed Description of the Invention The present invention relates to methods for treating or alleviating the symptoms of diffuse large cell lymphoma, comprising administering to a patient a therapeutically effective amount of an anti-CD20 antibody, or a therapeutically effective fragment thereof with a chemotherapy regime. The present invention also includes administering antibodies, and chemotherapy, as part of a transplant regimen (autologous bone marrow transplant or allogeneic bone marrow transplant or peripheral blood stem cell transplant) to improve the survival of transplant recipients.

Therapeutically effective antibody "fragments" refers to any portion of or derivative of an antibody that is capable of delivering substantially the same therapeutic effect as the whole antibody when administered to a patient having diffuse large cell lymphoma, or when used as part of a transplant regimen.

N:1Meboune\Cases PatmntrMO000-a99%fl222AU.1Spe-'P8o0222AU.1 SpecAl=icaon 2009.3-18.ckc: 183/O9 COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:42 FAX Q@0007/0052 0 0 N As the understanding of lymphoma improves and new histopathologic variations t are diagnosed, new classification systems for the different types of lymphoma have Semerged. In general, for the purposes of the methods described herein, intermediateo00 and high-grade lymphomas are defined as those designated in the "Working Formulation" established in 1982. This system includes as intermediate-grade lymphomas follicular large cell diffuse small cleaved cell (DSC), diffuse mixed O small and large cell and diffuse large cell, cleaved or noncleaved As high- 0 grade lymphomas, the system recognizes immunoblastic large cell (JBL), ,ilymphoblastic, convoluted or nonconvoluted and small noncleaved cell, Burkitt's (1 10 or non-Burkitt's (SNC).

SSeveral classification systems have emerged since the proposed Working o Formulation. For instance, a recent classification system proposed by European and American pathologists is called the Revised European American Lymphoma (REAL) Classification. Although this classification system does not use the terms "intermediate-" and "high-grade" NHL, it will be understood by those of skill in the art which lymphomas are typically characterized as "intermediate-" and "high-grade." For instance, "mantle cell lymphoma" as defined in the REAL classification system may appear as both indolent and more aggressive forms, and depending on the severity may be classified as an intermediate- or high-grade lymphoma.

For instance, the U.S. National Cancer Institute (NCI) has in turn divided some of the REAL classes into more clinically useful "indolent" or "aggressive" lymphoma designations. "Aggressive" lymphomas include diffuse mixed and large cell lymphoma, Burkitt's lymphoma/ diffuse small non-cleaved cell lymphoma, Lymphoblastic lymphoma, Mantle cell lymphoma and AIDS-related lymphoma. These lymphomas would therefor be considered at least "intermediate" or "high-grade," and would therefor benefit from the therapeutic methods of the present invention.

While strict classifications of some lymphomas may be difficult, the lymphomas treatable by the present invention .are generally characterized by a high number of circulating B cells, possible bone marrow involvement, bulky disease, or the involvement of extralymphatic organ or sites.

The patients administered the disclosed therapeutic methods are those patients who are refractory to or have relapsed from chemotherapy.

The methods of the present invention include methods comprising the administration of both monoclonal antibodies (or fragments thereof) to CD20 along with a chemotherapeutic regimen. Depending on the particular patient, said chemotherapy may be administered simultaneously or sequentially in either order.

"Simultaneously" means either concurrently or during the same time period such that N: ebIierCaesPaent\BO-8D99aP80222AU.11SpedskPB0222.AU.1 Spificmfio 2009-3-10.doc 18/03 9 COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:42 FAX 120008/0052 -6- C the circulating half-lives of the therapeutic agents overlaps.

Chemotherapeutic regimens which may be combined with the antibody treatments of the present invention include CHOP, ICE, Mitozantrone, Cytarabine, SDVP, ATRA, Idarubicin, hoelzer chemotherapy regime, La La chemotherapy regime, ABVD, CEOP, 2-CdA, FLAG IDA with or without subsequent G-CSF treatment), VAD, M P, C-Weekly, ABCM, MOPP and DHAP. The most preferred chemotherapeutic regimen is CHOP.

The primary anti-CD20 antibodies of the present invention are preferably human antibodies, or chimeric or humanized antibodies which are engineered with human 10 constant region domains, such that the antibodies are able to stimulate human effector functions. A preferred antibody to be used in the methods of the present invention is o Rituximab (IDEC Pharmaceuticals, Inc.).

Rituximab is one of a new generation of monoclonal antibodies developed to overcome limitations encountered with murine antibodies, including short half-life, limited ability to stimulate human effector functions, and immunogenicity. Rituximab is a genetically engineered monoclonal antibody with murine light- and heavy-chain variable regions and human gamma I heavy-chain and kappa light-chain constant regions. The chimeric antibody is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids and has an approximate molecular weight of 145 kD.

Rituximab is more effective than its murine parent in fixing complement and mediating ADCC, and it mediates CDC in the presence of human complement. The antibody inhibits cell growth in the B-cell lines FL-18, Ramos, and Raji, sensitizes chemoresistant human lymphoma cell lines to diphtheria toxin, ricin, CDDP, doxorubicin, and etoposide, and induces apoptosis in the DHL-4 human B-cell lymphoma line in a dose-dependent manner. In humans, the half-life of the antibody is approximately 60 hours after the first infusion and increases with each dose to 174 hours after the fourth infusion. The immunogenicity of the antibody is low; of 355 patients in seven clinical studies, only three had a detectable anti-chimeric antibody (HACA) response.

Autologous bone marrow transplantation is often a successful accompaniment to myeloablative therapy in helping to restore the immune system to patients who have undergone radiotherapy or chemotherapy. However, as discussed above, the patients who will benefit by the methods disclosed herein will often have lymphoma accompanied by bone marrow involvement. For such patients, there are often too many cancerous cells in the marrow to perform autologous transplantation.

When there is bone marrow involvement accompanying the intermediate- or N:VMelboume ,ePatenl80000-0a9W60222AU.1Spoecid%80222.AU.1 Specific an 2 0 093-IB.doc 18/0309 COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:42 FAX R0009/0052 0-7- CAq high-grade lymphoma, such patients may benefit by prior treatment with human, tchimeric or humanized anti-CD20 antibody before bone marrow harvesting in order to decrease the quantity of tumor cells in the bone marrow or stem cell preparation. In 00 fact, Rituximab can be administered at induction, in vivo purging, mobilization, conditioning, post-transplant reinfusion and at any other time during bone marrow or stem cell transplant for the purpose of improving the survival rate of transplant \recipients. "Induction" is meant to refer to the initial therapies aimed at achieving IN induction of remission. Typically, induction involves the administration of some type of chemotherapy,

CHOP.

(N 10 The phrase "in vivo purging" is meant to refer to treatment particularly geared otoward purging tumor cells from the bone marrow within the patient, although certainly osuch treatment might be beneficial for tumor cells in the peripheral blood and at other sites as well. Such a step may precede the harvest of bone marrow as a means of decreasing the number of tumor cells therein. Rituximab and other chimeric lymphoma cell-depleting antibodies provide an advantage in this regard over radiolabeled antibodies in that they may be used to purge the bone marrow of cancerous cells without damaging healthy progenitors.

"Mobilization" refers to the process by which stem cells are mobilized to leave the bone marrow and enter the circulatory system, and provides an alternative to bone marrow harvest per se as a source of stem cells for transplantation. Mobilization is typically achieved by administering a short burst of chemotherapy and/or growth factors. The growth factor G-CSF is commonly used, but others may be used according to the knowledge of the skilled artisan.

Typically, during mobilization, stem cells are separated from blood (which is then put back into the patient), and the stem cells are frozen until the patient is ready to be reinfused. Ex vivo purging with Rituximab, or other antibodies known in the art to be useful for this purpose, may then be used to deplete tumor cells in the stem cell preparation.

"Conditioning" refers to a process by which the patient is prepared to receive the autologous bone marrow reinfusion or allogeneic transplant. This is typically accomplished with a very high dose of chemotherapy in order to deplete all cells, both healthy cells and tumor cells, from the bone marrow. Chemotherapeutic drugs that may be given at sufficiently high doses without risking the patient's life, e.g.

cyclophosphamide, are known in the art.

Thus, with Rituximab treatment at the various stages of transplantation, marrow may be harvested prior to myeloablative radiotherapy, and reintroduced subsequent to such therapy with less concern about reintroducing tumor cells originally harvested N:\Melboume aSPatmtW000.099SPUf,2 a 3U n 2(09-3-1 Bsioe 18AO/O09 COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:43 FAX Q0010/0052 S-8i with the marrow back into the patient. Of course, the patient may then benefit by additional or subsequent treatment with chimeric anti-CD20 antibody as part of a maintenance regimen, or by administration of a radiolabeled antibody such as Y2B8 to further decrease the chance of relapse.

The methods of the present invention also encompass combined therapy comprising administration of at least one cytokine along with an anti-CD20 antibody or fragment thereof. Such a cytokine may be administered simultaneously or sequentially in any order. In particular, cytokines may be useful in upregulating the expression of on the surface of cancerous B cells prior to administration of the 10 antibody. Cytokines useful for this purpose include IL-4, GM-CSF and TNF-alpha, and Spossibly others.

p Cytokines may also be administered simultaneously or within the same time frame in order to increase or control certain effector functions mediated by the therapeutic antibody. Cytokines useful for this purpose include interferon alpha,

G-CSF

and GM-CSF, and possibly others.

Preferred dosage regimens and exemplary embodiments will now be illustrated by way of the following data.

Single---Agent Studies In a study conducted in Europe and Australia, alternative dosing schedules were evaluated in 54 relapsed or refractory intermediate- or high-grade NHL patients (Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister

A,

Feuring-Buske M, Radford JA, Capdevlle R, Diehl V, Reyes F. Rituximab monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase H study. Blood 1998; 92:1927-1932) Rituximab was infused at 375 mg/m 2 weekly for 8 doses or at 375 mg/m 2 once followed by 500 mg/m 2 weekly for 7 doses. The ORR was 31%; (CR PR 22%) no significant difference between the dosing regimens was observed. Patients with diffuse large-cell lymphoma 30) had an ORR of 37% and those with mantle-cell lymphoma (N 12) had an ORR of 33%.

Treatment of Bulky Disease Contrary to early assumptions about antibody therapy being useful only in micrometastatic disease, Rituximab is quite active in high bulk disease. In a separate study, 31 patients with relapsed or refractory, bulky low-grade NHL (single lesion of cm in diameter) received 375 mg/m 2 Rituximab as four weekly infusions. Twelve of 28 evaluable patients demonstrated a CR or PR (11, 39%) (Davis

T,

N:uWelbourneaseswat~M p9gPO222AU.IS,822.AU.1 Specimfcaion o200-3-Aac ag COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:43 FAX Q 0011/0052 O-9- White C, Grillo-L6pez A, Velasquez W, Link B, Maloney D, Dillman R, Williams M, Mohrbacher A, Weaver R, Dowden S, Levy R. Rituximab: First report of a Phase 1I (PI) trial in NHL patients (pts) with bulky disease. Blood 1998; 92 (10 Suppl 1): 4 14a). 0 0 This suggests that with the appropriate dosages depending on the extent of disease and the number of circulating tumor cells such as the increased dosages described above), Rituximab therapy will also be useful for more aggressive intermediate- or high-grade NHLs accompanied by bulky disease.

Combination of Rituximab and CHOP Chemothera v N0 In another study, 31 patients with intermediate- or high-grade NHL (19 females, 12 males, median age 49) received Rituximab on Day I of each of six 21 day cycles of CHOP Link B, Grossbard M, Fisher R, Czuezman M, Gilman P, Lowe A, Vose J. hase II pilot study of the safety and efficacy of Rituximab in combination with CHOP chemotherapy in patients with previously untreated- or high-grade NHL. Proceedings of the American Society of Clinical Oncology 1998; 17:3a). Of 30 evaluable patients there were 19 CR and 10 PR for an ORR of 96%. This regimen was considered well tolerated and may result in higher response rates than with Rituximab or CHOP alone.

The NCI Division of Cancer Treatment and Diagnosis is collaborating with IDEC Pharmaceuticals Corporation to explore Rituximab treatment in other indications.

A Phase II trial of CHOP versus CHOP and Rituximab is being conducted by ECOG, CALGB, and SWOG in older patients (>60 years) with mixed, diffuse large cell, and unmunoblastic large cell histology NHL (N 630 planned). This study includes a secondary randomization to maintenance with Rituximab versus nonmaintenance.

A Phase III trial of Rituximab and CHOP in 40 patients with previously untreated mantle-cell lymphoma is also ongoing at the Dana Farber Institute. Rituximab is administered on Day I and CHOP is given on Days 1 3 every 21 days for 6 cycles.

Accrual for this study has been completed. A Phase II trial of CHOP followed by Rituximab in newly diagnosed follicular lymphoma conducted by SWOG has also been completed. Results of these two trials are being analyzed.

A Phase II trial of CHOP and Rituximab versus CHOP alone in HIV-related NHL conducted by the AIDS Malignancy Consortium is ongoing; 120 patients are planned.

Rituximab after Mvloablative Therapy Relapse Rituximab has shown promising early results in patients with relapsed intermediate-grade NHL after high-dose therapy with autologous PBSC support. Six of N. a lelbomeCasesWaten00 80222.AU.1 pec 02 AU Specifiio 2009 -318.doc COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:43 FAX Q0012/0052 seven patients responded (1 CR and 5 PR) and one patient had stable disease; therapy was well tolerated (Tsai, D, Moore H, Porter D, Vaughn D, Luger S, Loh R, Schuster

S,

4 Stadtmauer E. Progressive intermediate grade non-Hodgkin's lymphoma after high dose therapy and autologous peripheral stem cell transplantation (PSCT) has a high response rate to Rituximab. Blood 1998; 9 2:415a, #1713).

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the Scommon general knowledge in Australia.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

N:\MelboumC PatentwMOOOO0999Pa0222U.1 SpecP S222AU., Specifiction 2 0093-18.doc 18o3a09i COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18

Claims (16)

1. A method for treating a patient with diffuse large cell lymphoma, comprising O administering to the patient a therapeutically effective amount of an antibody and a chemotherapeutic regimen; wherein the antibody is a chimeric, humanized, or human antibody comprising human constant regions, and is not conjugated to a toxin or radiolabel; IN) and wherein the patient is relapsed from or refractory to chemotherapy. 10 2. A method for treating a patient with relapsed or refractory diffuse large cell o lymphoma, comprising administering to the patient a therapeutically effective amount o of a human anti-CD20 antibody and a chemotherapeutic regimen, wherein the antibody is not conjugated to a toxin or radiolabel.

3. A method for treating a patient with diffuse large cell lymphoma accompanied by bulky disease, comprising administering to the patient a therapeutically effective amount of unlabeled Rituximab and CHOP chemotherapy.

4. A method for treating a patient with relapsed or refractory diffuse large cell lymphoma, comprising administering to the patient a therapeutically effective amount of unlabeled Rituximab and CHOP chemotherapy. Use of an anti-CD20 antibody in the preparation of a medicament for treating a patient with diffuse large cell lymphoma, wherein the antibody is a chimeric, humanized, or human antibody comprising human constant regions, and is not conjugated to a toxin or radiolabel; wherein the patient is relapsed from or refractory to chemotherapy; and wherein the medicament is for administration of a therapeutically effective amount of the antibody to the patient along with a chemotherapeutic regimen.

6. Use of a human anti-CD20 antibody in the preparation of a medicament for treating a patient with relapsed or refractory diffuse large cell lymphoma, wherein the antibody is not conjugated to a toxin or radiolabel, and the medicament is for administration of a therapeutically effective amount of the antibody to the patient along with a chemotherapy regimen.

7. Use of unlabeled Rituximab in the preparation of a medicament for treating a N:\MelboJm«Cases\PatenB O999 0222.AU,1 SpecsV>80222.AU.1 Specfication 2009-3-Ia.ckx 18/03/09 COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:43 FAX I0014/0052 -12- cpatient with diffuse large cell lymphoma accompanied by bulky disease, wherein the medicament is for administration of a therapeutically effective amount of Rituximab with CHOP chemotherapy. 00

8. Use of a therapeutically effective amount of tmlabeled Rituximab in the preparation of a medicament for treating a patient with relapsed or refractory diffuse large cell lymphoma, wherein the medicament is for administration of a therapeutically Va effective amount of Rituximab together with CHOP chemotherapy.

9. The method of any one of claims I to 4 or the use of any one of claims 5 to 8, wherein the patient is refractory to chemotherapy. The method of any one of claims I to 4 or the use of any one of claims 5 to 8, wherein the patient has relapsed from chemotherapy.

11. The method of any one of claims I to 4, wherein the chemotherapeutic regimen or CHOP chemotherapy is administered with the antibody simultaneously.

12. The method of any one of claims 1 to 4, wherein the chemotherapeutic regimen or CHOP chemotherapy and antibody are administered sequentially in any order.

13. The use of any one of claims 5 to 8, wherein the patient is administered the medicament at the same time as the chemotherapeutic regimen or CHOP chemotherapy.

14. The use of any one of claims 5 to 8, wherein the chemotherapeutic regimen or CHOP chemotherapy and medicament are administered sequentially in any order. The method of claim 1 or claim 2 or the use of claim 5 or claim 6, wherein the chemotherapeutic regimen is CHOP.

16. The method of claim 1 or claim 2 or the use of claim 5 or claim 6, wherein the chemotherapeutic regimen is ICE.

17. The method of claim I or claim 2 or the use of claim 5 or claim 6, wherein the chemotherapeutic region is DHAP.

18. The method of claim 1 or claim 2 or the use of claim 5 or claim 6, wherein the N:V1elbxume -asePatentD8000

222-AU-l$Peft\'e222U.1 Spe:ifn,n 2O09-3-18.do 1M03109 COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:44 FAX R0015/0052 o -13- 0 rl antibody is a chimeric antibody. 19. The method of claim 18, wherein the chimeric antibody is Rituximab. 00 20. The method of claim 1 or claim 2 or the use of claim 5 or claim 6, wherein the antibody is a humanized antibody. a\ NO 21. The method of claim 1 or claim 2 or the use of claim 5 or claim 6, wherein the antibody is a human antibody. CN1 o 22. The method of any one of claims 1 to 4 or the use of any one of claims 5 to 8, o wherein the lymphoma is accompanied by bone marrow involvement. 23. The method of any one of claims 1 to 4, further comprising bone marrow or stem cell transplantation. 24. The use of any one of claims 5 to 8, wherein the patient is further treated by bone marrow or stem cell transplantation. 25. The method of any one of claims I to 4, further comprising administering at least one cytokine to the patient. 26. The use of any one of claims 5 to 8, wherein the patient is further treated by administration of at least one cytokine. 27. The method of claim 25 or the use of claim 26, wherein the cytolkine is interferon alpha, G-CSF, GM-CSF, IL-4, or TNF-alpha. 28. The method of any one of claims 1 to 4, wherein the antibody is administered to the patient as part of a post-transplant maintenance regimen. 29. The use of any one of claims 5 to 8, wherein the medicament is for administering as part of a post-transplant maintenance regimen. 30. The method of any one of claims 1, 2 or 4 or use of any one of claims 5, 6 or 8, wherein the lymphoma is accompanied by bulky disease. N-lMalbourio'CasesAatenBOOO099OB 8a222-AU-l\SleosJ\P80222AU.1 Specffcation 20093-1-B8Oc 1&03/09i COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date 2009-03-18 18/03 2009 12:44 FAX 0016/0052 -14- 31. The method of any one of claims 1 to 4 or use of any one of claims 5 to 8 substantially as hereinbefore described, with reference to the Examples. l:Me'IUbmexCasePatenVMO0r..,eQ222-A22 w %pecis'Pw.1 Spedficafon 204-3-1odo 18/03f09 COMS ID No: ARCS-227558 Received by IP Australia: Time 12:48 Date

2009-03-18