Cancer Treatment

Maintenance Rituxan for CLL.

Rituximab has been shown to prolong survival when used therapeutically with chemotherapy in CLL. This Rituximab, the mAb targeting CD20, was approved by the US FDA for patients with relapsed low-grade non-Hodgkin lymphoma. Relatively low levels of CD20 are expressed on CLL B cells, compared to normal B or neoplastic B cells of other lymphomas. In addition, soluble CD20 has been demonstrated in plasma of patients with CLL; this may inhibit the capacity of rituximab to bind to CLL B cells, thereby resulting in rapid clearance and negatively affecting pharmacokinetics. Standard-dose rituximab (375 mg/m2 weekly for 4 weeks) has very limited activity for patients with CLL. Dose-intense and dose-dense single-agent rituximab has been shown to increase efficacy but remains experimental. Rituxan at standard dose  is  listed by NCCN as a single agent only for frail patients who cannot tolerate other treatments. A 2005 guideline (Imre et al) says: "There is currently insufficient evidence to support or refute the additional use of rituximab as a maintenance therapy in patients who have completed chemotherapy plus rituximab." However, NCCN doest list it as a single agent for the elderly.A recent guideline (Imre et al) says: "There is currently insufficient evidence to support or refute the additional use of rituximab as a maintenance therapy in patients who have completed chemotherapy plus rituximab."

Since this guideline, additional evidence has accrued to support rituximab for maintenance in CLL. The strongest evidence in support of it was the Primary Rituximab and Maintenance (PRIMA) Study, in which patients received immunochemotherapy. Those who did not fail were randomly assigned to maintenance or observation. There was a longer progression-free survival in those who received rituximab maintenance, but no survival benefit. There also was the  Ardeshna study, in which patients who could be observed were either randomly assigned to the watch-and-wait approach or to rituximab induction and maintenance. Time to requiring next treatment was longer if you got rituximab, but there was no survival benefit.

Currently(2012) are no guidelines that recommend maintenance rituximab.

The IMiDs, thalidomide and lenalidomide, have also been investigated as maintenance treatment in CLL. Lenalidomide might have some validity as maintenance treatment and clinical trials of lenalidomide in maintenance treatment have been initiated.

Imrie K, Stevens A, Meyer R, Hematology Disease Site Group. Rituximab in lymphoma and chronic lymphocytic leukemia: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Dec 22. 46 p. (Evidence-based series; no. 6-8). [65 references]

Kahl BS, Hong F, Williams ME, et al. Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. Program and abstracts of the 53rd American Society of Hematology Annual Meeting and Exposition; December 10-13, 2011; San Diego, California. Abstract LBA-6.

Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled. Lancet. 2011;377:42-51. Abstract

Ardeshna KM, Qian W, Smith P, et al. An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2 and 3a): a preliminary analysis. Program and abstracts of the 52nd American Society of Hematology Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida. Abstract 6.

Sher T, Miller KC, Lawrence D, et al. Efficacy of lenalidomide in patients with chronic lymphocytic leukemia with high-risk cytogenetics. Leuk Lymphoma. 2010;51:85-88.

Rituxan for CD20 positive myeloma

Interest in using Rituxan for subsets of myeloma with CD20 positivity, was provoked by a Phase II study of Moreau et al evaluating four weekly infusions of single-agent rituximab (375 mg/m2) therapy in a cohort of patients with CD20+ multiple myeloma (MM) with either stage I, never treated disease, or stage III MM in relapse, or refractory after two lines of therapy. The authors concluded that rituximab as a single agent had minor activity in this cohort of patients with CD20 expression on at least 33% of tumor cells. A 2008 review concluded: "Clinical trials show that anti-CD20 therapy with rituximab elicits a partial response in approximately 10% of CD20+ patients with multiple myeloma. In addition, there is preliminary evidence of disease stabilization in 50-57% of CD20+ patients for a period of 10-27 months. Further large-scale clinical trials are therefore needed to establish the role of this promising strategy in the treatment of myeloma." There are several other reports in different settings, including in maintenance.

All in all, there is sufficient literature to consider it supported.

J M Bergua, C Cabrera, E G Arteta and J Prieto
Rituximab in CD20 positive multiple myeloma, Letter to the Editor, Leukemia 22, 1082-1083 (May 2008)

P Moreau, L Voillat, L Benboukher, C Mathiot, C Dumontet, N Robillard, O Hérault, F Garnache, R Garand, N Varoqueaux, H Avet-Loiseau, J L Harousseau and R Bataille
Rituximab in CD20 positive multiple myeloma, Leukemia 21, 835-836 (April 2007)

Kapoor P, Greipp PT, Morice WG, Rajkumar SV, Witzig TE, Greipp PR.
Anti-CD20 monoclonal antibody therapy in multiple myeloma.
Br J Haematol. 2008 Apr;141(2):135-48. Epub 2008 Mar 3.

Long-term response to maintenance treatment with rituximab in CD20+ multiple myeloma
Hitoshi OhnoLeukemia & Lymphoma
November 2010, Vol. 51, No. 11 : Pages 2144-2146

 

Rituximab for rheumatoid artritis

 

Rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other disease-modifying anti-rheumatic drugs (DMARDs), including treatment with at least one tumour necrosis factor alpha (TNF-alpha) inhibitor therapy. This combination treatment is FDA indicated.

However, in a situation in which ,methotrexate is contraindicated, literature supports Rituxan alone. In the phase II trial, the ACR responses of patients treated with rituximab in combination with MTX (ACR20, ACR50 and ACR70: 73%, 43% and 23%, respectively) were numerically superior to those receiving rituximab monotherapy (65%, 33% and 15%, respectively). As the difference between responses to rituximab monotherapy and the placebo control arm (ACR20, ACR50 and ACR70: 38%, 13% and 5%, respectively) did not reach statistical significance for ACR50 and ACR70 responses14 (category Ib), rituximab is licensed only in combination with MTX.  Nevertheless, rituximab monotherapy was also shown to be more effective (ACR20 response) than placebo (category Ib).

National Institute for Health and Clinical Excellence (NICE). Rituximab for the treatment of rheumatoid arthritis. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Aug. 26 p. (Technology appraisal guidance; no. 126).

J S Smolen, E C Keystone, P Emery, F C Breedveld, N Betteridge, G R Burmester, M Dougados, G Ferraccioli, U Jaeger, L Klareskog, T K Kvien, E Martin‐Mola, and K Pavelka, The Working Group on the Rituximab Consensus StatementConsensus statement on the use of rituximab in patients with rheumatoid arthritis, Ann Rheum Dis. 2007 February; 66(2): 143–150.

Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T.
Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.N Engl J Med. 2004 Jun 17;350(25):2572-81.

Rituxan for Wegener's

Wegener's granulomatosis (WG) is a chronic, multisystem disease, characterized by a small vessel vasculitis. First line therapy is cyclophosphamide. Despite the use of other immunosuppressive agents, including methotrexate, azathioprine and mycophenolate mofetil, to maintain remission, relapse often occurs – with many patients requiring further courses of cyclophosphamide over many years.

Rituximab is being tested in a wide variety of small vessel vascultides but no prospective studies have been done in any of them, to my knowlledge. One pilot trial for Wegener's showed a high response rate in a small group of patients. However, there was also the RAVE trial which became the basis for the FDA approval. The U.S. Food and Drug Administration approved Rituxan (rituximab), in combination with glucocorticoids (steroids) on April 12, 2011 to treat patients with Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA), two rare disorders that cause blood vessel inflammation (vasculitis).

Alistair J. Ferraro , Clara J. Day , Mark T. Drayson , and Caroline O. Savage
Effective therapeutic use of rituximab in refractory Wegener's granulomatosis
Nephrol. Dial. Transplant. 20: 622-625

C M G Cheung, P I Murray, and C O S Savage
Successful treatment of Wegener's granulomatosis associated scleritis with rituximab
Br J Ophthalmol, November 1, 2005; 89(11): 1542 - 1542.

K. A. Keogh, S. R. Ytterberg, F. C. Fervenza, K. A. Carlson, D. R. Schroeder, and U. Specks Rituximab for Refractory Wegener's Granulomatosis: Report of a Prospective, Open-Label Pilot Trial
Am. J. Respir. Crit. Care Med., January 15, 2006; 173(2): 180 - 187.

Despina Eleftheriou , Marianna Melo , Stephen D. Marks , Kjell Tullus , John Sills , Gavin Cleary , Pavla Dolezalova , Seza Ozen , Clarissa Pilkington , Pat Woo , Nigel Klein , Michael J. Dillon , and Paul A. Brogan
Biologic therapy in primary systemic vasculitis of the young
Rheumatology Advance Access published on August 1, 2009, DOI 10.1093/rheumatology/kep148.
Rheumatology 48: 978-986.

Rituxan for follicular lymphoma

Rituximab (Rituxan®) is a monoclonal antibody that has been used to treat various cancers of the blood (leukemia) and the lymphatic system (lymphoma). Rituximab (given with cyclophosphamide, vincristine and prednisolone), the R-CVP regimen, is recommended as a possible treatment for people with symptomatic stage III or IV follicular lymphoma who haven't been treated before. It has been used successfully, both alone and in combination with standard chemotherapy, in patients whose follicular lymphoma has recurred or proven resistant to other treatment. The addition of rituximab to first-line chemotherapy has been found to improve survival of patients with previously untreated follicular lymphoma. R-CVP was used for this patient.

Data from five clinical trials in patients with follicular lymphoma whose disease had relapsed or was resistant to treatment show those who received maintenance therapy with rituximab survived longer than those who did not receive maintenance therapy. However, this finding leaves unanswered the question of whether maintenance rituximab is superior to treatment with rituximab on relapse. However, it is being recommended by the Cochrane Database. NCCN lists single agent Rituxan for maintenance on p. 68.

Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, Cohen A, Shpilberg O. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials.J Natl Cancer Inst. 2009 Feb 18;101(4):248-55.

Vidal L, Gafter-Gvili A, Leibovici L, Shpilberg O.Rituximab as maintenance therapy for patients with follicular lymphoma.Cochrane Database Syst Rev. 2009 Apr 15;(2)

nccn.org, follicular, p. 27

Rituxan for Castleman's

Castleman's disease, also called angiofollicular lymph node has two forms, localized and a multicentric. The clinical and biological signs are varied and heterogeneous, and the diagnostic is made on the histologic examination. There are no expert assessment, guidelines or consensus statements, policy statements or formal technology assessments for this disease.

Not much has been published about RItuxan in Castleman's Disease, aside from case reports. Rituximab may be clinically valuable as initial therapy for HIV-associated multicentric Castleman disease. However, in two human immunodeficiency virus-infected patients who needed etoposide therapy to control exacerbations of Castleman disease and received four infusions of rituximab, clinical and virologic relapses with increased blood human herpesvirus-8 DNA levels occurred in both patients 4 and 24 weeks later and were associated with a worsening of Kaposi sarcoma. On the other hand, Rituximab was both effective and safe in a small prosepctive study of HIV-infected patients with chemotherapy-dependent Multicentri Casteleman's Disease. Since the literature is conflicting and only a small phase II study supports it, Rituxan should be considered experimental at this time.

Bower M, Powles T, Williams S, Davis TN, Atkins M, Montoto S, Orkin C, Webb A, Fisher M, Nelson M, Gazzard B, Stebbing J, Kelleher P. Brief communication: rituximab in HIV-associated multicentric Castleman disease.Ann Intern Med. 2007 Dec 18;147(12):836-9.

Neuville S, Agbalika F, Rabian C, Brière J, Molina JM. Failure of rituximab in human immunodeficiency virus-associated multicentric Castleman disease.Am J Hematol. 2005 Aug;79(4):337-9.

Gérard L, Bérezné A, Galicier L, Meignin V, Obadia M, De Castro N, Jacomet C, Verdon R, Madelaine-Chambrin I, Boulanger E, Chevret S, Agbalika F, Oksenhendler E.Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's disease: ANRS 117 CastlemaB Trial.Clin Oncol. 2007 Aug 1;25(22):3350-6.

Rituxan: Prevention of post-transplant lymphoproliferative disorders

Anti-CD20 (Rituximab) is a humanised monoclonocal antibody directed against the specific CD20 antigens found on B lymphocytes plasma membrane. It has been approved by the FDA for the treatment of lymphoma and post-transplant lymphoproliferative diseases. The rationale for using Rituxan for treating EBV infections is that it can destroy B cells and thus "dampen" T-cell response caused by immune dysregulation. After bone marrow transplantation (BMT) using T-cell-depleted marrow from an unrelated donor or HLA-mismatched related donor, the risk of developing lymphoproliferative disease associated with the Epstein-Barr virus (EBV) ranges from 1% to 25%. Although this medicine has been approved by the Food and Drug Administration to treat patients with other types of lymphomas, and has been used to treat a small number of patients with EBV lymphomas and other types of B-cell leukemias, it has not been approved to try and prevent EBV-lymphomas. Use of Rituximab to try to prevent EBV-lymphomas is therefore experimental.

Results of a recent study are awaited: Rituximab (Rituxan) for the Prevention of EBV-LPD Epstein Barr Virus (EBV) Lymphoproliferative Disorder Post T Cell Depleted Unrelated and HLA Mis-Matched Related HSCT,NCT00648037 Ingrid Kuehnle, M. Helen Huls, Zhensheng Liu, Micah Semmelmann, Robert A. Krance, Malcolm K. Brenner, Cliona M. Rooney, and Helen E. Heslop
CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation
Blood 95: 1502-1505.

Gruhn B; Meerbach A; Häfer R; Zell R; Wutzler P; Zintl F
Pre-emptive therapy with rituximab for prevention of Epstein-Barr virus-associated lymphoproliferative disease after hematopoietic stem cell transplantation.
Bone marrow transplantation 2003;31(11):1023-5.

Rituxan for pemphigus

Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous blistering disease. Conventional therapy consists of high-dose corticosteroids, immunosuppressive agents, and intravenous immune globulin. More recently newer agenst, such as Cellcept and Dapsone. Among the new approaches is Rituxan. A number of case reprots suggest that Rituxan is an effective reatment but it had not been prospectively studies.FOr example, a recent report of 11 pateitns treated with Rituxan adn IVIG, showed that of 11 patients, 9 had rapid resolution of lesions and a clinical remission lasting 22 to 37 months (mean, 31.1). All immunosuppressive therapy, including prednisone, could be discontinued before ending rituximab treatment in all patients. Two patients were treated with rituximab only during recurrences and had sustained remissions.

Rituxan as been rapidly adopted and is now extensively used. Aetna considers it appropriate in steroid refractory diseae, which this is. There are no FDA approved therapies for this disease and Rituxan is off-label and therefore by defintion, experimental. It is med. necessary as outlined above.Harman KE, Albert S, Black MM. Guidelines for the management of pemphigus vulgaris. Br J Dermatol 2003 Nov;149(5):926-37.

Ahmed, A. Razzaque, Spigelman, Zachary, Cavacini, Lisa A., Posner, Marshall R.
Treatment of Pemphigus Vulgaris with Rituximab and Intravenous Immune Globulin
N Engl J Med 2006 355: 1772-1779
 
Diaz, Luis A.
Rituximab and Pemphigus -- A Therapeutic Advance
N Engl J Med 2007 357: 605-607
 
Noah ScheinfeldA review of rituximab in cutaneous medicine
Dermatology Online Journal 12 (1): 3

.Mao X, Payne AS.Seeking approval: present and future therapies for pemphigus vulgaris.Curr Opin Investig Drugs. 2008 May;9(5):497-504

Oxaliplatin and Rituxan for Hodgkin's

Rituxan is a promising drug for Hodgkin's but more studies need to be done. Oxaliplatin is currrently in a clinical trial: Oxaliplatin in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma., NCT00006473, completed but not published yet. It is a Phase II trial to study the effectiveness of oxaliplatin in treating patients who have relapsed or refractory non-Hodgkin's lymphoma.

According to results recently published in the journal Blood, Rituxan® (rituximab) appears to be a promising agent in the treatment of some patients with recurrent Hodgkin's. Rituxan® is a monoclonal antibody approved for treatment of non-Hodgkin’s lymphoma (NHL) and binds to an antigen called CD 20. A small subset of patients with Hodgkin’s lymphoma (3% to 8%) has a type of cancer called CD 20 lymphocyte predominant Hodgkin’s lymphoma, characterized by a large proportion of their cancer cells expressing CD 20. Patients with CD 20 lymphocyte predominant Hodgkin’s lymphoma tend to have a higher rate of recurrence following standard therapy than other patients with Hodgkin’s lymphoma. 

Researchers from Germany recently conducted a clinical trial to evaluate the effectiveness of Rituxan® in the treatment of recurrent Hodgkin’s lymphoma. The trial involved 14 patients with CD 20 lymphocyte predominant Hodgkin’s lymphoma, or Hodgkin’s lymphoma with over 30% of their cancer cells expressing CD 20. Patients were on average 9 years from diagnosis and had stopped responding to at least one prior therapy. Overall, 12 patients had an anti-cancer response to Rituxan®, with 8 patients achieving a complete disappearance of detectable cancer and 4 patients achieving a partial anti-cancer response. Two patients had progressive disease. One year following therapy, 9 of the 12 responding patients demonstrated no signs of cancer progression. Furthermore, at over 20 months following therapy, the average duration of responses has not yet been reached. Side effects were generally mild and moderate, allowing for the majority of patients to receive treatment on an outpatient basis.

The researchers concluded that Rituxan® is a viable treatment option for patients with relapsed Hodgkin’s lymphoma that expresses the CD 20 antigen clinical trials.

Combination of the two was recenlty tried in 8 elderly relapsed/ reefractory patients. One complete response, 3 partial response and 3 minimal response were obtained at 11 months of median time follow-up.

The combination of these two drugs with gemcitabine has recently been reported as well in a single phase II study. Rituximab, gemcitabine and oxaliplatin are active as single agents in relapsed or refractory lymphoma, and have demonstrated synergistic effects in vitro and in vivo.

In summary, there are two Phase II trials that demonstrate some effectiveness of Rituxan in a specific subset of Hodgkin’s Lymphoma. First, it needs to be determined if the patient has lymphocyte predominant disease. Most plans will consider this therapy to be investigational but where coverage is availble it is certainly an interesting and promising option.

Rehwald U, Schultz H, Reiser M, et al. Treatment of relapsed CD20+ Hodgkin lymphoma with monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood. 2003;101:420-424.

Rehwald U, Schulz H, Reiser M, et al. German Hodgkin Lymphoma Study Group (GHSG): treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood. 2003;101: 420-424.

D. Re, R. K. Thomas, K. Behringer, and V. Diehl
From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential
Blood, June 15, 2005; 105(12): 4553 - 4560.

Addeo R, Caraglia M, Costanzo R, Faiola V, Montella L, Abbruzzese A, Del Prete S. Oxaliplatin/rituximab combination in the treatment of intermediate-low grade non-Hodgkin's lymphoma of elderly patients. Oncol Rep. 2004 Jul;12(1):135-40

T El Gnaoui , J Dupuis , K Belhadj , J-P Jais , A Rahmouni , C Copie-Bergman , I Gaillard , M Diviné , I Tabah-Fisch , F Reyes , and C Haioun Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy
Annals of Oncology Advance Access published on August 1, 2007, DOI 10.1093/annonc/mdm133.
Ann Oncol 18: 1363-1368.

 

R-ASHAP regimen for salvage of lymphoma

R-ASHAP chemotherapy is - rituximab, doxorubicine, methylprednisolone, high-dose cytarabine, cisplatin. This is fairly new regimen  with only a few reports of observational studies.

There are no randomized controlled trials comparing different conventional dose salvage chemotherapy regimens (PACEBOM, ESHAP, RICE, IVAC) in people with relapsed aggressive non-Hodgkin's lymphoma. The consensus is that people with relapsed disease should be treated with salvage chemotherapy. One systematic review identified 22 phase II trials of various conventional dose salvage chemotherapy regimens. All regimens reported similar response rates and no single superior regimen can be identified. There are likewise no studies confirming or disproving the additive effect of Rituximab but it is a well reported regimen and no clinical trials are currently investigating RICE vs ICE chemotherapy.However, it is not proven. A clinical trial (NCT00367497) of R-ESHAP is currently recruiting patients.

B. J. Byrne and J. P. Gockerman Salvage Therapy in Hodgkin's Lymphoma
Oncologist, February 1, 2007; 12(2): 156 - 167.

J. Rodriguez, M.A. Rodriguez, L. Fayad, P. McLaughlin, F. Swan, A. Sarris, J. Romaguera, B. Andersson, F. Cabanillas, and F.B. Hagemeister
ASHAP: A Regimen for Cytoreduction of Refractory or Recurrent Hodgkin's Disease
Blood 93: 3632-3636.

Aydin, Semra; Dührsen, Ulrich; Nückel, Holger, Rituximab plus ASHAP for the treatment of patients with relapsed or refractory aggressive non-Hodgkin's lymphoma: a single-centre study of 20 patients Source: Annals of Hematology, Volume 86, Number 4, April 2007 , pp. 271-276(6)

Hänel M, Kröger N, Hoffknecht MM, Peters SO, Metzner B, Fiedler F, Braumann D, Schubert JC, Illiger HJ, Hänel A, Krüger WH, Zeller W, Weh HJ, Hossfeld DK, Zander AR. ASHAP--an effective salvage therapy for recurrent and refractory malignant Ann Hematol. 2000 Jun;79(6):304-11.

MEHMET AKIF ÖZTÜRK et al,  Modified ESHAP as salvage chemotherapy for recurrent or refractory non-Hodgkin's lymphoma: Results of a single-center study of 32 patients Chemotherapy  (Chemotherapy)  2002, vol. 48, no5, pp. 252-258

BMJ - CLinical Evidence - http://clinicalevidence.bmj.com/ceweb/conditions/bly/2401/2401_I5.jsp

Kimby E, Brandt L, Nygren P, et al. A systematic review of chemotherapy effects in aggressive non-Hodgkin's lymphoma. Acta Oncol 2001;40:198–212. 

Barosi G, Carella A, Lazzarino M, et al. Management of nodal diffuse large B-cell lymphomas: practice guidelines from the Italian Society of Haematology, the Italian Society of Experimental Haematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2006;91:96–103.

http://clinicaltrials.gov/ct/show/NCT00367497;jsessionid=9202040C24BA6886B737A55F632A7F7A?order=3

Kimby E, Brandt L, Nygren P, et al. A systematic review of chemotherapy effects in aggressive non-Hodgkin's lymphoma. Acta Oncol 2001;40:198–212.