From www.bloodjournal.org at US PATENT TRADEMARK OFFC on October 8, 2008. For personal use only.
`
`2004 104: 2269-2271
`Prepublished online May 27, 2004;
`doi :10.1182/blood-2004-03-1091
`Antitumor activity of rituximab plus thalidomide in patients with
`relapsed/refractory mantle cell lymphoma
`
`Hannes Kaufmann, Markus Raderer, Stefan Wohrer, Andreas POspok, Alexander Bankier, Christoph
`Zielinski, Andreas Chott and Johannes Drach
`
`Updated information and services can be found at:
`http://bloodjoumal.hematologylibrary.org/cgi/content/full/104/8/2269
`Articles on similar topics may be found in the following Blood collections:
`Neop1asia (4156 articles)
`lmmunotherapy (577 articles)
`Clinical Trials and Observations (2446 articles)
`
`Information about reproducing this article in parts or in its entirety may be found online at:
`http://bloodjoumal.hematologylibrary.org/misc/rights.dtl#repub ____ requests
`
`Information about ordering reprints may be found online at:
`http://bioodjoumal.hematologyiibrary.org/misc/rights.dtl#reprints
`
`Information about subscriptions and ASH membership may be found online at:
`http://bioodjoumal.hematologylibrary.org/subscriptions/index.dtl
`
`Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published
`semimonthly by the American Society of Hematology, 1900 M St, NW, Suite
`200, Washington DC 20036.
`Copyri~1t1t 2007 by Tt1e American Society of Hematology; all rights reserved.
`
`IPR2018-00685
`Celgene Ex. 2010, Page 1
`
`

`

`From www.bloodjournal.org at US PATENT TRADEMARK OFFC on October 8, 2008. For personal use only.
`
`CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
`
`Antitun1or activity of rituximab plus thalidonlide in patients
`with relapsed/refractory n1antle cell lymphoma
`
`Hannes Kaufmann, Markus Raderer, Stefan Wohrer, Andreas Puspok, Alexander Bankier,
`Christoph Zielinski, Andreas Chott, and Johannes Drach
`
`We evaluated a treatment strategy target(cid:173)
`ing both lymphoma cells {by rituximab)
`and the microenvironment {by thalido(cid:173)
`mide) in 16 patients with relapsed/refrac(cid:173)
`tory mantle cell lymphoma {MCL). Ritux(cid:173)
`imab was administered at 375 mg/m2 for 4
`weekly doses concomitantly with thalido(cid:173)
`mide {200 mg daily, with a dose increment
`to 400 mg on day 15), which was contin(cid:173)
`ued as maintenance therapy until progres-
`
`sion/relapse. Thirteen patients {81%) ex(cid:173)
`perienced an objective response, with 5
`complete responders {31%). Median pro(cid:173)
`gression-free survival {PFS) was 20.4
`months {95% confidence interval [Cl],
`17.3-23.6 months), and estimated 3-year
`survival was 75%. In patients achieving a
`complete response, PFS after rituximab
`plus thalidomide was longer than PFS
`after the preceding chemotherapy. Se-
`
`vere adverse events included 2 thrombo(cid:173)
`embolic events and 1 grade IV neutrope(cid:173)
`nia associated with thalidomide. Our
`results suggest that rituximab plus tha(cid:173)
`lidomide has marked antitumor activity in
`relapsed/refractory MCL and a low toxic(cid:173)
`ity profile, which warrants further evalua(cid:173)
`tion in MCL. {Blood. 2004;104:2269-2271)
`
`© 2004 by The American Society of Hematology
`
`Patient characteristics
`
`All 16 patients (Table 1) enrolled into this phase 2 protocol had already
`been treated by CHOP (cyclophosphamide, hydroxydaunorubicin, Onco(cid:173)
`vin, prednisone; n = 14) or a CHOP-like regimen (n = 2). Fifteen
`patients were at relapse (7 patients after 2 or more prior regimens), 1
`patient was primary refractory to CHOP. Two patients had prior
`high-dose chemotherapy with autologous transplantation, and 1 patient
`underwent an allogeneic stem cell transplantation after reduced(cid:173)
`intensity conditioning. Three patients had prior rituximab (single-agent
`rituximab at relapse in 2 patients, and rituximab plus CHOP [R-CHOP]
`as induction treatment in 1 patient). Median time between initial
`diagnosis of MCL and initiation of study treatment was 21 months
`(range, 4-52 months). Each patient gave written informed consent prior
`to study inclusion.
`
`Introduction
`Mantle cell lymphoma (MCL), which represents a distinct Study design
`clinicopathologic entity among the non-Hodgkin lymphomas, is
`characterized by a low response rate to and short progression(cid:173)
`free survival (PFS) after conventional chemotherapy. L2 Admin(cid:173)
`istration of high-dose therapy with autologous stem cell rescue
`has also not resulted in long-term disease-free survival of
`patients with MCL, l,H emphasizing the need for novel treat(cid:173)
`ment strategies for this lymphoma entity. It has been recognized
`that stromal cells deliver important stimuli for growth and
`survival of normal and malignant B cells.5•6 Interactions be(cid:173)
`tween tumor and stromal cells can be modulated by agents like
`thalidomide and proteasome inhibitors. Activity of thalidomide
`has already been demonstrated in B-cell malignancies, in
`particular multiple myeloma7•8 and \Valdenstri:im macroglobuline(cid:173)
`mia.9 In a patient with heavily pretreated and rapidly progres(cid:173)
`sive MCL, we have observed stabilization of the disease for a
`period of 6 months following administration of thalidomide
`(J.D., unpublished observation, September 2000). We, therefore,
`hypothesized that a treatment strategy targeting both lymphoma
`cells and the microenvironment could be active in MCL. \Ve
`evaluated this treatment approach in patients with MCL pre(cid:173)
`treated with chemotherapy and combined thalidomide with
`rituximab, an antibody with documented efficacy in MCL. t 0
`
`Treatment regimen
`
`Treatment with rituximab consisted of 4 weekly doses at 375 mg/m2, with
`standard premedication (diphenhydramine and paracetamol). Thalidomide
`was started on the evening of day 1 (scheduled daily dose, 200 mg during
`the first 2 weeks, then 400 mg) and continued as maintenance treatment
`after completion of rituximab until progression or relapse. The study
`protocol was approved by the institutional ethics committee.
`
`From the Department of Medicine I, Clinical Division of Oncology, University
`Hospital Vienna; the Department of Medicine IV, University Hospital Vienna:
`the Department of Radiology, University Hospital Vienna; and the Department
`of Pathology, University Hospital Vienna. Vienna, Austria.
`
`Submitted March 23, 2004: accepted May 10, 2004. Prepublished online as
`Blood First Edition Paper. May 27. 2004; DOI 10.1182/blood-2004-03-1091.
`
`Supported in part by grants from CLEXO (Excellence Center of Clinical and
`Experimental Oncology at the University Hospital Vienna) and the Lymphoma
`
`Research Founda1ion.
`
`Reprints: Johannes Drach, University Hospital Vienna, Department of
`Medicine I. Clinical Division of Oncology, Waehringer Guertel 18-20, A-1090
`Vienna, Austria; e-mail: johannes.drach@meduniwien.ac.a1.
`
`The publication cos1s of this article were defrayed in part by page charge
`payment Therefore. and solely to indicate this fact, this article is hereby
`marked "advertisement'· in accordance with 18 U.S.C. section 1734.
`
`© 2004 by The American Socie1y of Hematology
`
`BLOOD, 15 OCTOBER 2004 • VOLUME 104, NUMBER 8
`
`2269
`
`IPR2018-00685
`Celgene Ex. 2010, Page 2
`
`

`

`From www.bloodjournal.org at US PATENT TRADEMARK OFFC on October 8, 2008. For personal use only.
`
`2270
`
`KAUFMANN et al
`
`BLOOD, 15 OCTOBER 2004 • VOLUME 104, NUMBER 8
`
`Table 1. Dose of thalidomide actually administered in patients with MCL
`
`Patient
`
`Age, y*
`
`IPI
`
`Response
`
`Maximum
`
`During maintenance
`
`Thalidomide dose, mg
`
`2
`3
`4
`5
`6
`7
`8
`g
`
`10
`11
`12
`13
`14
`15
`16
`
`56
`68
`50
`70
`74
`65
`64
`70
`74
`71
`62
`45
`76
`64
`72
`61
`
`Jrrtermediafo-low
`I ntermed i ate-high
`Low
`Intermediate-high
`Jl'ltermediate)-high
`Intermediate-high
`](1termedi"11E\-high
`lntermed iate-low
`Mterrned iate:-low
`High
`Jrrtermediale,.high
`Low
`High
`Intermediate-low
`Jlitermediat,How
`High
`
`PR
`PR
`CR
`PR
`CR
`CRu
`PR
`SD
`CR
`PR
`PR
`CR
`NR
`PR
`NR
`PR
`
`400
`400
`400
`400
`400
`200
`200
`400
`200
`200
`200
`200
`200
`200
`200
`200
`
`200 (121'1k) -,, 100 (26 wk)-,, 50 (88wk, continued d~ring tetreaimeht)
`400 (8 wk)----, 300 (4 wk)----, 200 (47 wk)----, 100 (19 wk, continued during retreatment)
`400 (70Wk) ~200 (8 wk,coniinued during retteatment)
`400 (8 wk) ----, 300 (8 wk; discontinued because of neutropenia)
`400(8wk)-->300(15wk)-200(32Wk)-> 100(361'!k)
`200 (36 wk)----> 100 (42 wk)----, 50 (22 wk; discontinued because of neuropathy)
`200 (3 wk) -,, 10c, (83 wk)
`400 (8 wk)----, 200 (15 wk)
`200(2Dwk) -,,100 (60wk} -,,50(5!5+ wk)
`200 (36 wk)----, 100 (20 wk)
`20(i(32.l'lk) --;.100 (44+ 'Nk)
`100 (8 wk)----, 50 (44-s- wk)
`100(8wk)
`200 (20wk)
`2.00(8wk)
`200(12+wk)
`
`IPI indicates International Prognostic Index; SD, stable disease; and NR, no response.
`*Age at the time of initiation of study treatment.
`
`Toxicity was assessed weekly during the first month of treatment and
`thereafter once a month during thalidomide-maintenance with use of
`standard National Cancer Institute common toxicity criteria. Response to
`treatment was assessed according to the International Workshop Response
`Criteria Guidelines,11 with restaging every 3 months. PFS and overall
`survival (OS) was estimated by the method of Kaplan and Meier.
`
`Results and discussion
`
`Response
`
`Objective responses to rituximab plus thalidomide (R + T) were
`achieved in 13 of the 16 patients ( overall response rate, 81 %;
`95% CI, 59.8%-102.7%), l patient experienced stable disease.
`Five patients (31%; 95% CI, 5.7%-56.8%) achieved a complete
`response (CR; 4 CR, l unconfirmed/uncertain complete remis(cid:173)
`sion [CRu]), including the patient with primary CHOP(cid:173)
`resistance and l patient at relapse after autologous transplanta(cid:173)
`tion. Eight patients (50%; 95% CI, 22.5%-77.5%) had a partial
`response (PR); among them was the patient after allogeneic
`transplantation with reduced-intensity conditioning. Responses
`were observed both at nodal and extranodal manifestations of
`MCL (remission of gastrointestinal manifestations in 5 patients,
`disappearance of a lymphoma in the breast in 1 patient). In
`responding patients, shrinkage of peripheral lymph nodes and/or
`significant improvements of laboratory parameters ( clearance
`
`of lymphoma cells in the peripheral blood in 3 patients,
`hematologic improvement, reduction of elevated serum levels of
`lactate dehydrogenase [LDH]) were noted during the first month
`of treatment.
`Among the 13 responders, 8 patients experienced a relapse or
`progressive disease. In 3 of them, l course of rituximab (4 weekly
`infusions at 375 mg/m2) was again added to thalidomide as
`reinduction treatment. Second remissions were induced in 2 of
`them, and PFS was 18+ months (versus 20 months after the first
`administration of R + T) and 13 months (versus 30 months),
`respectively.
`
`Progression-free and overall survival
`
`Median PFS of the 16 patients was 20.4 months (95% CI, 17.6-23.6
`months; Figure 1), as opposed to 12.7 months after the line of
`chemotherapy preceding R + T. Improvement of PFS after R + T
`was particularly evident among the 5 patients achieving a CR
`(Figure lC). Median OS has not yet been reached, with 13 patients
`alive at the time of analysis (February 22, 2004) and an estimated
`3-year survival of75%.
`
`Toxicity
`
`It was assumed that combination of R + T should not lead to added
`toxicity, which was confirmed during the course of this trial. All
`
`5
`
`11)
`
`1 :: _ 11 JI~.
`
`3
`
`6
`5
`P<>li&:i!lsc.
`
`Figure 1. Progression-free survival. (A) Progression-free (median, 20A months; solid line) and overall survival (dashed line) of patients with relapsed/refractory MCL from
`the time of initiation of rituximab plus thalidomide. (B) Progression-free survival after rituximab plus thalidomide (median. 20A months; solid line) was significantly longer
`compared with progression-free survival after the previous line of chemotherapy (median, 12.7 months; dashed line) (P ~ .027), (C) Progression-free survival (PFS) of patients
`with MCL achieving a CR after rituximab plus thalidomide (a) compared with PFS after the previous line of chemotherapy (D).
`
`IPR2018-00685
`Celgene Ex. 2010, Page 3
`
`

`

`From www.bloodjournal.org at US PATENT TRADEMARK OFFC on October 8, 2008. For personal use only.
`
`BLOOD, 15 OCTOBER 2004 • VOLUME 104, NUMBER 8
`
`RITUXIMAB + THALIDOMIDE IN RELAPSED/REFRACTORY MCL
`
`2271
`
`patients completed the scheduled 4 infusions of rituximab. Infu(cid:173)
`sional reactions to rituximab, consisting of fever, rigors, and chills
`(grades I-II), developed in 7 patients (44% ), mainly during the first
`application, but no other adverse events (grade II or greater) were
`encountered.
`Fatigue, somnolence, and constipation were common, dose(cid:173)
`dependent side effects of thalidomide; therefore, the planned dose
`of 400 mg daily could only be achieved in 6 patients, and it was
`necessary to adapt the maintenance dose of thalidomide on an
`individual basis (Table 1). A daily dose of 50 to 200 mg could be
`maintained with only limited toxicity, which was also reported by
`Damaj et al.1 2 Peripheral neuropathy (grades I-II) occurred in 7
`patients ( 44% ). Because of neuropathy, 1 patient discontinued
`thalidomide after 30 months. Grade IV neutropenia associated with
`thalidomide was observed in 1 patient, and his neutrophil counts
`recovered after discontinuation of thalidomide. As previously
`reported, there were 2 events of venous thromboembolism13 (1
`deep-vein thrombosis 5 weeks after initiation of therapy, and one
`asymptomatic pulmonary embolism at routine computed tomogra(cid:173)
`phy [CT] scanning during follow-up).
`The efficacy of R + Tis clearly beyond that of rituximab alone
`(35% remission rate of single-agent rituximab in patients with
`MCL, with virtually no CR and a median PFS of 12 months),10,14,15
`and its activity compares favorably with results of other salvage
`strategies in MCL. For example, among 21 evaluable patients with
`relapsed MCL, the recently reported R-FCM (rituximab, fludara(cid:173)
`bine, cyclophosphamide, mitoxantrone) regimen induced remis(cid:173)
`sions in 13 patients (62% ), with a CR in 7 patients (33% ). 16 As
`
`recently published in 2 case reports, 12.17 thalidomide has single(cid:173)
`agent activity in relapsed MCL, and we can now assume that it may
`be additive to or synergistic with rituximab. Thalidomide is known
`to have pleiotropic effects,18 which mainly exert an indirect effect
`on tumor cells by modulating cytokine secretion19 and expression
`of adhesion molecules, 20 and by enhancing the activity of natural
`killer (NK) cells and cytotoxic T lymphocytes.21·22 It is worth
`noting that rituximab can induce cytotoxic T-cell responses against
`lymphoma-associated antigens in vitro,23 an effect that could be
`further enhanced by the immunomodulatory activity of thalido(cid:173)
`mide. Finally, effects of thalidomide on the microenvironment also
`include inhibition of angiogenesis.24 Further studies are required to
`delineate the precise mechanism of action of thalidomide in MCL.
`Despite the limited number of patients, our study provides
`evidence for promising antitumor activity and a low toxicity profile
`of R + T in patients with relapsed/chemotherapy refractory MCL.
`The observation of durable remissions warrants further evaluation
`in an attempt to improve the overall grim prognosis in MCL. \Ve
`are, therefore, studying rituximab plus CHOP plus thalidomide as
`induction treatment, followed by thalidomide maintenance, in
`patients with previously untreated MCL.
`
`Acknowledgment
`
`\Ve thank Dr K. Zwingenberger (Gruenenthal GmbH. Aachen,
`Germany) for providing thalidomide for this study.
`
`References
`
`1. Campo E, Raffeld M, Jaffe ES. Mantle-cell lym-
`phoma. Semin Hematol. 1999:36:115-126.
`2. Hiddemann W, Unterhalt M. Herrmann R. et al.
`Mantle cell lymphomas have more widespread
`disease and a slower response to chemotherapy
`compared with follicle-center lymphomas: results
`of a prospective comparative analysis of the Ger-
`man Low-Grade Lymphoma Study Group. J Clin
`Oneal. 1998:16:1922-1930.
`
`3. Freedman A, Neuberg D. Gribben J, etal. High-
`dose chemo-radiotherapy and anti-B-cell mono-
`clonal antibody-purged autologous bone marrow
`transplantation in mantle cell lymphoma: no evi-
`dence for long-term remission. J Clin Oneal.
`1998:16:13-18.
`4. Gopal AK, Rajendran JG, Petersdorf SH, et al.
`High-dose chemo-radioimmunotherapy with au-
`tologous stem cell support for relapsed mantle
`cell lymphoma. Blood. 2002;99:3158-3162.
`5. Manabe A, Murti KG, Coustan-Smith E, et al. Ad-
`hesion-dependent survival of normal and leuke-
`mic human B lymphoblasts on bone marrow stro-
`mal cells. Blood. 1994;83:758-766.
`6. Merville P. Dechanet J, Desmouliere A, et al.
`Bcl-2+ tonsillar plasma cells are rescued from
`apoptosis by bone marrow fibroblasts. J Exp
`Med. 1996;183:227-236.
`
`7. Singhal S, Mehta J. Desikan R, et al. Antitumor
`activity of thalidomide in refractory multiple my-
`eloma. N Engl J Med. 1999:341 :1565-1571.
`
`8. Strasser K, Ludwig H. Thalidomide treatment in
`multiple myeloma. Blood Rev. 2002;16:207-215.
`
`9. Dimopoulos MA, Zomas A, Viniou NA. et al.
`Treatment of Waldenstrom's macroglobulinemia
`
`with thalidomide. J Clin Oneal. 2001; 19:3596-
`3601.
`10. Foran JM, Cunningham D, Coiffier B, et al. Treat-
`men! of mantle cell lymphoma with rituximab (chi-
`meric monoclonal anti-CD20 antibody): analysis
`of factors associated with response. Ann Oneal.
`2000;11 :117-121.
`11. Cheson B, Horning S, Coiffier B, et al. Report of
`an International Workshop to standardize re-
`sponse criteria for non-Hodgkin's lymphomas.
`J Clin Oneal. 1999;17:1244-1253.
`12. Damaj G, Lefrere F, Delarue R, Varet B, Furman
`R, Hermine 0. Thalidomide therapy induces re-
`sponse in relapsed mantle cell lymphoma. Leuke-
`mia. 2003;17:1914-1915.
`13. Urbauer E, Kaufmann H, Nosslinger T, Raderer
`M, Drach J. Thromboembolic events during treat-
`ment with thalidomide. Blood. 2002;99:4247-
`4248.
`14. Coiffier B, Haioun N, Ketterer N, et al. Rituximab
`(anti-CD20 monoclonal antibody) for the treat-
`ment of patients with relapsing or refractory ag-
`gressive lymphoma: a multicenter phase II study.
`Blood. 1998;92:1927-1932.
`15. Ghielmini M, Schmitz SF, Burki K, et al. The effect
`of rituximab on patients with follicular and mantle
`cell lymphoma. Swiss Group for Clinical Cancer
`Research (SAKK).Ann Oneal. 1999;11(suppl 1):
`S123-S126.
`16. Dreyling MH, Forstpointner R. Repp R. et al.
`Combined immuno-chemotherapy (R-FCM) re-
`suits in superior remission and survival rates in
`recurrent follicular and mantle cell lymphoma:
`final results of a prospective randomized trial of
`the German Low Grade Lymphoma Study Group
`
`(GLSG) [abstract]. Blood. 2003;102:103a. Ab-
`stract no. 351.
`17. Wilson EA, Jobanputra R, Jackson R. Parker AN,
`McQuaker IG. Response to thalidomide in che-
`motherapy-resistant mantle cell lymphoma: a
`case report. BrJ Haematol.2002;119:128-130.
`18. Raje N, Anderson K. Thalidomide, a revival story.
`N Engl J Med. 1999;341: 1606-1609.
`19. Corral LG, Haslett PA, Muller GW. et al. Differen-
`tial cytokine modulation and T cell activation by
`two distinct classes of thalidomide analogues that
`are potent inhibitors of TN F-alpha. J lmmunol.
`1 999; 1 63 :380-386.
`20. Settles B, Stevenson A, Wilson K, et al. Down-
`regulation of cell adhesion molecules LFA-1 and
`ICAM-1 after in vivo treatment with the anti-TN F-
`alpha agent thalidomide. Cell Mal Biol. 2001 :47:
`1105-1114.
`21. Haslett PAJ, Corral LG, Albert M, Kaplan G. Tha-
`lidomide costimulates primary human T lympho-
`cytes, preferentially inducing proliferation, cyto-
`kine production, and cytotoxic responses in the
`CD8- subset. J Exp Med. 1998:187:1885-1892.
`22. Davies FE, Raje N, Hideshima T, et al. Thalido-
`mide and immunomodulatory derivatives aug-
`men! natural killer cell cytotoxicity in multiple my-
`eloma. Blood. 2001;98:210-216.
`23. Selenko N, Maidic 0. Draxier S, et al. CD20 anti-
`body (C2B8)-induced apoptosis of lymphoma
`cells promotes phagocytosis by dendritic cells
`and cross-priming of CDS+ cytotoxic T cells. Leu-
`kemia. 2001 ;15:1619-1626.
`24. D'Amato RJ. Loughnan MS. Flynn E, Folkman J.
`Thalidomide is an inhibitor of angiogenesis. Proc
`Natl Acad Sci U SA. 1994;91 :4082-4085.
`
`IPR2018-00685
`Celgene Ex. 2010, Page 4
`
`