AU2005211669C1

AU2005211669C1 - Treatment of intermediate- and high-grade non-Hodgkins lymphoma with anti-CD20 antibody

Info

Publication number: AU2005211669C1
Application number: AU2005211669A
Authority: AU
Inventors: Antonio Grillo-Lopez; Christine A. White
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1999-08-11
Filing date: 2005-09-23
Publication date: 2017-09-21
Anticipated expiration: 2020-08-02
Also published as: AU2005211669A1; AU2005211669B2

Abstract

This invention discloses methods for the treatment of intermediate- and high-grade non Hodgkins lymphomas comprising administration of anti-CD20 antibodies.

Description

18/03 2000 12:41 FAX )0004/0052 2005211669 18 Mar 2009 -2·

Treatment k>f Intermediate- and High-Grade Lymphoma with Anti-CD20 Antibody

Non-Hodgkins

This application is a 5 67478/00 the specification and herein in their entirety by referei .p ional plication of Australian Application No. drawings of which as originally filed are incorporated e. 10

Field of the Invention The present invention co: with anti-CD20 monoclonal anti 4 (cems methods of treating diffuse large cell lymphoma >odies and fragments thereof.

Background of the Invention Non-Hodgkin’s lymphonda is characterized by the malignant growth of B lymphocytes. According to the A merican Cancer Society, an estimated 54,000 new 15 cases will be diagnosed, 65% of1 yhich will be classified as intermediate- or high-grade lymphoma. Patients diagnosed with intermediate-grade lymphoma have an average survival rate of 2-5 years, and patients diagnosed with high-grade lymphoma survive an average of 6 months to 2 years af :er diagnosis. Intermediate- and high-gr ide lymphomas are much more aggressive at the time 20 of diagnosis than are low-grade 1; mphomas, where patients may survive an average of 5-7 years with conventional thera lies. Intermediate- and high-grade lymphomas are often characterized by large extra aodal bulky tumors and a large number of circulating cancer cells, which often infiltrate the bone marrow of the patient. Conventional therapies ha re included chemotherapy and radiation, possibly 25 accompanied by either autologous or allogeneic bone marrow or stem cell transplantation if a suitable donor is available, and if the bone marrow contains too many tumor cells upon harvesting. While patients often respond to conventional therapies, they usually relapse wit hin several months. A relatively new approach to treating non-Hodgkin’s lymphoma has been to 30 treat patients with a monoclonal a atibody directed to a protein on the surface of cancerous B cells. The antibody n tay be conjugated to a toxin or radiolabel thereby affecting cell death after binding. Alternatively, an antibody may be engineered with human constant regions such that luman antibody effector mechanisms are generated upon antibody binding which resu It in apoptosis or death of the cell. 35 One antibody currently bei ng investigated for the treatment of intermediate- and high-grade lymphomas is Oncolyr i® (l3,I-Lym-l)(Techniclone Corp.), which is a murine IgG2a monoclonal antibod y which recognizes the HLA-DrlO protein which is N:\Melboume\Ca! es\Patann8000a^0909\P90222.AU.1\Sped^F8D222^U.1 Specification 20O9-3-18.doc 13/03/09 COMS ID No: ARCS-227558 Received by IP Australia: Time (H:m) 12:48 Date (Y-M-d) 2009-03-18 3 2005211669 22 Dec 2016 present on the surface of over 80% of lymphoma cells. Only 2% of normal B cells (noncancerous) express the HLA-DrlO molecule. Oncolym® is conjugated to a Iodine-[311(131I), a radioactive isotope of iodine which emits ta irradiation for a distance of several millimeters, and is thereby thought to be an effective approach to targeting the outer rim of tumors and halting the progression of bulky disease.

However, a potential disadvantage in using Oncolym® in advanced forms of non-Hodgkin's lymphoma is that such lymphomas are often characterized by bone a marrow involvement. Thus, administration of a radiolabeled antibody to such patients often results in unwanted myelosuppression and damage to healthy progenitor cells.

It would be advantageous if alternative therapies and other monoclonal antibodies could be administered to patients with intermediate- and high-grade lymphomas which circumvent some of the deficiencies associated with current treatments and decrease the frequency of relapse.

Summary of Invention

The present invention concerns the use of anti-CD20 antibodies for the treatment of diffuse large cell lymphoma. In particular, the present inventors have surprisingly found that Rituximab, a chimeric anti-CD2 antibody already approved for the treatment of low-grade follicular non-Hodgkin's lymphoma is effective to treat diffuse large cell lymphoma in combination 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, comprising administering to the patient a therapeutically effective amount of an anti-CD20 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; and wherein the patient is relapsed from or refractory to chemotherapy

In a second aspect, the invention provides a method for treating a patient with relapsed or refractory diffuse large cell lymphoma, comprising administering to the patient a therapeutically effective amount of a human anti-CD20 antibody and a chemotherapeutic regimen, where n the antibody is not conjugated to a toxin or radiolabel.

In a third aspect, the invention provides 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, wherein the CHOP chemotherapy is administered simultaneously with the Rituximab.

In a fourth aspect, the invention provides 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. 2005211669 22 Dec 2016 4

In 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 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.

In a sixth aspect, the invention provides 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.

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 simultaneously 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.

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As the understanding of lymphoma improves and new histopathologic variations are diagnosed, new classification systems for the different types of lymphoma have emerged. In general, for the purposes of the methods described herein, intennediate-and high-grade lymphomas are defined as those designated in the “Working 5 Formulation” established in 1982. This system includes as intermediate-grade lymphomas follicular large cell (FL), diffuse small cleaved cell (DSC), diffuse mixed small and large cell (DM), and diffuse large cell, cleaved or noncleaved (DL). As high-grade lymphomas, the system recognizes immunoblastic large cell (IBL), lymphoblastic, convoluted ornonconvoluted (LL), and small noncleaved cell, Burkitt’s to or non-Burkitt’s (SNC).

Several classification systems have emerged since the proposed Working Formulation. For instance, a recant 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 15 “intermediate-” and “high-grade” NHL, it will be understood by those of skill in die 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. 20 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 25 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 30 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 35 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^MeibOume\Cases)Patent\80000<8O999VP8O222AU.1\Sped3VP8Q222.AU.1 Specification 2009-3-IB.doc 18/03/09 COMS ID No: ARCS-227558 Received by IP Australia: Time (H:m) 12:48 Date (Y-M-d) 2009-03-18

18/03 2009 12:42 FAX 0008/0052 2005211669 18 Mar 2009 -6- the circulating half-lives of the therapeutic agents overlaps.

Chemotherapeutic regimens which maybe combined with the antibody treatments of the present invention include CHOP, ICE, Mitozantrone, Cytarabine, DVP, ATRA, Idarubicin, hoelzer chemotherapy regime, La La chemotherapy regime, 5 ABVD, CEOP, 2-CdA, FLAG & IDA with or without subsequent G-CSF treatment), VAD, Μ & 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 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, 15 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 20 145 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, 25 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 (<1%) had a detectable anti-chimeric 30 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 35 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 t_ N:\Mdbwjme\Ca^\P3<ent\80000-80eaitPB0222.AIJ.1\Sp«ieiP80222.AU.1 Specification 2O09-3-fS.<Joc 1&Ώ3Φ9 COMS ID No: ARCS-227558 Received by IP Australia: Time (H:m) 12:48 Date (Y-M-d) 2009-03-18

18/03 2009 12:42 FAX 8) 0009/0052 2005211669 18 Mar 2009 - 7 - high-grade lymphoma, such patients may benefit by prior treatment with human, chimeric 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, hi fact, Rituximab can be administered at induction, in vivo purging, mobilization, 5 conditioning, post-transplant remfusion 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 induction of remission. Typically, induction involves the administration of some type of chemotherapy, i.e., CHOP. 10 The phrase “in vivo purging” is meant to refer to treatment particularly geared toward purging tumor cells from the bone marrow within Ihe patient, although certainly such 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 15 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 tbe circulatory system, and provides an alternative to bone 20 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 foe skilled artisan.

Typically, during mobilization, stem cells are separated from blood (which is 25 then put back into the patient), and foe stem cells are frozen until the patient is ready to be reinfused. Ex vivo purging with Rituximab, or other antibodies known in foe art to be useful for this purpose, may then be used to deplete tumor cells in foe stem cell preparation. “Conditioning” refers to a process by which the patient is prepared to receive foe 30 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 foe bone marrow. Chemotherapeutic drugs that may be given at sufficiently high doses without risking foe patient’s life, e.g. cyclophosphamide, are known in foe art. 35 Thus, with Rituximab treatment at foe various stages of transplantation, marrow may be harvested prior to myeloablatdve radiotherapy, and reintroduced subsequent to such therapy with less concern about reintroducing tumor cells originally harvested tt\lfelbOufne*Cases\PafentV8000(MW999\F80222AU.1lSpec&Fa0222ALL1 Spedftcat&l 2009*3-1 &doc 1840309 COMS ID No: ARCS-227558 Received by IP Australia: Time (H:m) 12:48 Date (Y-M-d) 2009-03-18

18/03 2009 12:43 FAX 00010/0052 2005211669 18 Mar 2009 -8- 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. 5 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 upiegulating the expression of CD20 on the surface of cancerous B cells prior to administration of the anti-CD20 10 antibody. Cytokines useful for this purpose include IL-4, GM-CSF and TNF-alpha, and possibly others.

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 15 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 20 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, Capdeville R, Diehl V, Reyes F. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory 25 aggressive lymphoma: a multicenter phase H study. Blood 1998; 92:1927-1932).

Rituximab was infused at 375 mg/m2 weekly for 8 doses or at 375 mg/m2 once followed by 500 mg/m2 weekly for 7 doses. The ORR was 31%; (CR 9%, PR 22%) no significant difference between the dosing regimens was observed. Patients with diffuse large-cell lymphoma (N = 30) had an ORR of 37% and those with mantle-cell 30 lymphoma (N = 12) had an ORR of 33%.

Treatment of Balkv 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 35 study, 31 patients with relapsed or refractory, bulky low-grade NHL (single lesion of >10 cm in diameter) received 375 mg/m2 Rituximab as four weekly infusions. Twelve of 28 evaluable patients (43%) demonstrated a CR (1,4%) or PR (11, 39%) (Davis T, l N:Metboume\Cases\Patenf\8OOCK^80999\P80222AU.1 \Spoas'Pe0222.AU.1 Spedliralion 20O8-S-1i.doc 18/03Λ» COMS ID No: ARCS-227558 Received by IP Australia: Time (H:m) 12:48 Date (Y-M-d) 2009-03-18

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White C, Grillo-Lopez A, Velasquez W, Link B, Maloney D, Diliman R, Williams M, Mohrbacher A, Weaver R, Dowden S, Levy R. Rituximab: First report of a Phase Π (ΡΠ) trial in NHL patients (pts) with bulky disease. Blood 1998; 92 (10 Suppl l):414a).

This suggests that with the appropriate dosages depending on the extent of 5 disease and the number of circulating tumor cells (i.e., 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 Chemotherapy 10 In another study, 31 patients with intermediate- or high-grade NHL (19 females, 12 males, median age 49) received Rituximab on Day 1 of each of six 21 - day cycles of CHOP Link B, Grossbard M, Fisher R, Czuczman M, Gilman P, Lowe A, Vose J. Phase Π pilot study of the safety and efficacy of Rituximab in combination with CHOP chemotherapy in patients with previously untreated- or high-grade NHL. Proceedings 15 of the American Society of Clinical Oncology 1998; 17:3a). Of30 evaluable patients, there were 19 CR (63%) and 10 PR (33%), 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 20 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 immunoblastic large cell histology NHL (N = 630 planned). This study includes a secondary randomization to maintenance with Rituximab versus nonmaintenance. 25 A Phase HI 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 Π trial of CHOP followed by Rituximab in newly diagnosed follicular lymphoma conducted by SWOG has also been 30 completed. Results of these two trials are being analyzed. A Phase Π trial of CHOP and Rituximab versus CHOP alone in HIV-related NHL conducted by the AIDS Malignancy Consortium is ongoing; 120 patients are planned. 35 Rituximab after Mveloablative 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:\Melbovn>eVCases\RatennfiO000-60999V’60222AU.1\$peci^P80222AU.1 Specification 2009-3*18.doe 18/03Φ9 COMS ID No: ARCS-227558 Received by IP Australia: Time (H:m) 12:48 Date (Y-M-d) 2009-03-18

18/03 2009 12:43 FAX @0012/0052 2005211669 18 Mar 2009 -10- 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, Lugcr S, Loh R, Schuster S, Stadtmauer E. Progressive intermediate grade non-Hodgkin’s lymphoma after high dose therapy and autologous peripheral stem cell transplantation (PSCT) has a high response 5 rate to Rituximab. Blood 1998; 92:415a, #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 common general knowledge in Australia.

Throughout this specification and the claims which follow, unless the context 10 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:vMelboume«^ses\Paten»\800CK>^0999HP8O222AU.1\Specls\Pea222.AU.t SpecfliceGixt 20Q9-3-18.doc 18/0&09 COMS ID No: ARCS-227558 Received by IP Australia: Time (H:m) 12:48 Date (Y-M-d) 2009-03-18

Claims

1. A method for treating a patient with diffuse large cell lymphoma, comprising 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; and wherein the patient is relapsed from or refractory to chemotherapy.

2. A method for treating a patient with relapsed or refractory diffuse large cell lymphoma, comprising administering to the patient a therapeutically effective amount 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, wherein the CHOP chemotherapy is administered simultaneously with the Rituximab.

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.

5. 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 patient with diffuse large cell lymphoma accompanied by bulky disease, wherein the medicament is for administration of a therapeutically effective amount of Rituximab simultaneously with CHOP chemotherapy.

8. 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.

9. The method of any one of claims 1 to 4 or the use of any one of claims 5 to 8, wherein the patient is refractory to chemotherapy.

10. The method of any one of claims 1 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 1 2, or 4, wherein the chemotherapeutic regimen or CHOP chemotherapy is administered with the antibody simultaneously.

12. The method of any one of claims 1, 2 or 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, 6 or 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, 6 or 8, wherein the chemotherapeutic regimen or CHOP chemotherapy and medicament are administered sequentially in any order.

15. 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 antibody is a chimeric antibody.

19. The method of claim 18, wherein the chimeric antibody is Rituximab.

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.

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.

22. The method of any one of claims 1 to 4 or the use of any one of claims 5 to 8, wherein die 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 1 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 cytokine 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.

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.