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悪性リンパ腫に対する新薬の開発動向と展望
小椋美知則
Key words : Lymphoma, New drugs, Molecular targeted drugs, Cytotoxic agents
臨床試験:単剤での phase I studyinotuzumab ozogamicin (CMC-544)の初めての臨床試
験成績として,米国および日本から各々 phase I studyの結果が相次いで,2010年に発表された4, 5)。
①米国における phase I study:再発・難治の CD22陽性 B-NHL症例の 79症例{男女比は 47/32,年齢中央値 60歳(範囲;26∼82歳),
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名古屋第二赤十字病院 血液・腫瘍内科
第 75回日本血液学会学術集会
リンパ系腫瘍:ALL/MLEL-31 プログレス
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Table 1 Developmental status of new drugs in lymphomas in Japan
Category Drug CharacteristicsTarget
moleculeStudy status in Japan Target population
MoAb inotuzumab ozogamicin(CMC-544, INO)
Calicheamicin conjugated humanized anti-CD22 MoAb
CD22 • Phase I of single agent, and phase I of CMC-544+rituximab; completed global phase II study of rituximab in rituximab-refractory FL; completed
• global phase I study of R-CVP-CMC-544; on going• global phase I study of R-GDP-CMC-544; on going• global randomized phase III of R-CMC-544 vs R-bendamustine
in relapsed DLBCL; on going• randomized phase III study of CMC-544 vs conventional
chemotherapies in relapsed/refractory ALL; on going
Relapsed/refractory B-NHL or B-ALL
MoAb ofatumumab Humanized anti-CD 20 MoAb CD20 • Phase I; completed• Phase I/II; completed• global randomized phase III of ofatumumab vs rituximab in
relapsed FL; on going • phase I study of ofatumumab+chlorambucil in newly
diagnosed CLL; on going• global randomized phase III of R-DHAP vs Ofatumumab-DHAP
in relapsed DLBCL; on going • global phase III study of bendamustine vs ofatumumab+
bendamustine in Rituximab-refractory FL; on going
Relapsed/refractory B-NHL, CLL
MoAb GA-101(obinutuzumab)
Humanized anti-CD20 MoAb CD20 • Phase I;completed• Global randomized Phase III study of R-CHOPvs GA101-CHOP
in newly diagnosed DLBCL; on going• Global randomized Phase III study of R-CHOP, R-CVP,
R-bendamustine vs GA101-CHOP in newly diagnosed FL; on going
臨床試験:inotuzumab ozogamicin と rituximab の併用の phase I study
① inotuzumab ozogamicinと rituximabの併用 phase I試
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Fig. 1 Structural formula of inotuzumab ozogamicin. Inotuzumab ozogamicin(CMC-544) is a targeted chemotherapy agent composed of ahumanized anti-CD22 antibody conjugated to calicheamicin, a potentcytotoxic antibiotic.
Fig. 2 (A) Tumor response at end of treatment for all pa-tients in dose-escalation cohorts and for all patientswith follicular lymphoma and diffuse large B-cell lym-phoma (DLBCL) receiving maximum-tolerated dose(MTD) treatment (lead-in cohort, n/5; expandedMTD cohort, n/43). Objective response rate (ORR)included complete response (CR), unconfirmed com-plete response (CRu), and partial response. Kaplan-Meier curves of (B) progression-free survival (PFS)and (C) overall survival (OS) for all patients in theexpanded MTD cohort. (Ref. 4)
Table 2A Response of CMC544 in Japanese phase I study(Ref. 5)
Tumor responses were determined by the investigator according to the International Response Criteria for Non-Hodgkin Lymphoma. Tumor assessments occurred approximately every eight weeks during treatment(or sooner), at the end of treatment visit, and every 12 weeks during follow-up visits. Overall response included complete confi rmed, complete unconfi rmed and partial response. DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MALT, mucosa-associated lymphoid tissue; MCL, mantle cell lymphoma.
Table 3 Response of inotuzumab ozogamicin in rituximab-refractory indolent B-NHL(Ref. 7)
ITT, intent-to-treat; FL, follicular lymphoma; MZL, mantle zone lymphoma; SLL, small lymphocytic leukemia; ORR, overall response rate.Assessment of response and progression status were evaluated according to the International Response Criteria for Non-Hodgkin's Lymphomas.
Table 4 Comparison of humanized anti-CD20 monoclonal antibodies including obinutuzumab, ofatumumab and AME-133
Product Description ADCC CDC Apoptosis Binding
3rd GenerationAnti-CD20
GA-101(GlycArt/Roche)
•Humanized•Enhanced binding to FcyRIIIA• B-cell depletion superior to Rituxan in
murine models
HuMaX-CD20Ofatumumab
(GenMab/GSK)
•Human IgGl kappa(Medarex)•Unique but overlapping binding site•Phase I/II for NHL and CLL•Kills RTX-resistant cell lines• Depletes B cells in cynos(peripheral
blood & lymph nodes)•50% B-CLL killing vs. 5% RTX(in vitro)
(3x─10x) Slower off-rates
AME-133(AME/Ell Lilly)
•Humanized• Optimized via proprietary AME process(improved FcyRIII binding and ADCC)•10-fold higher cell killing vs. RTX ─10x
Table 6B Effi cacy of brentuximab vedotin in relapsed/refractory ALCL in phase II study(Ref. 23)
MeasureResponse(N=58)
95% CI
Objective response rate, % 86 74.6 to 93.9 CR rate* 57 43.2 to 69.8 Partial remission rate 29Stable disease, % 3Progressive disease, % 5Histologically ineligible, %† 3Not evaluable, % 2Median duration of objective response, months 12.6 5.7 to NEMedian duration of response in patlents with CR, months 13.2 10.8 to NEMedian progression-free survival, months 13.3 6.9 to NEMedian overall survival, months Not reached 14.6 to NE
Abbreviations: CR, complete remission; NE, not estimable.* All patients with CR had evidence of a postbaseline fluorodeoxyglucose-negative position
emission tomography scan, with the exception of one patient who achieved complete resolution of disease by computed tomogra- phy scan at a time point when position emission tomography scans were not required per protocol.† Patients who did not confirm a diagnosis of anaplastic large-cell lymphoma by central
pathology assessment; patients were scored as nonresponders in the analysis(n=2).
Table 6A Effi cacy of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma in phase II study(Ref. 22)
ParameterNo. of
Patients(N=102)
%
Objective response 76 75 Complete remission 35 34 Partial remission 41 40Stable disease 22 22Progressive disease 3 3Not evaluable 1 1Duration of objective response, months Median 6.7 95% CI 3.6 to 14.8Duration of response for patients with complete remission, months(n=35) Median 20.5 95% CI 10.8 to NEProgression-free survival, months Median 5.6 95% CI 5.0 to 9.0Overall survival, months Median 22.4 95% CI 21.7 to NE
Abbreviation: NE, not estimable.
果たしていることから,こうした bortezomibによる奏効例は予想されていた26)。1例に grade 4の低ナトリウム血症が認められ,最も頻度の多い grade 3の毒性はリンパ球減少(14例)と血小板減少(7例)であり耐容性が確認された。bortezomib (1.5 mg/m2を day 1,4,8,11に静注投与)は FL,MCL,MZLに対して有効であり,現在は欧米で rituximabなどとの併用での臨床試験が進められている。Fisherらは,155例の治療抵抗性もしくは再発性のMCLに対する bortezomibの phase II studyの成績を発表した27)。1.3 mg/m2を 3週間間隔で day 1,4,8,11に投与して,17サイクルまで継続投与を行った結果,141例の評価可能症例において奏効割合 33%,完全奏効割合 8%で,奏効期間中央値は 9.2ヶ月であった。観察期間中央値 13.4ヶ月で,増悪までの期間(time-toprogression)中央値は 9.2ヶ月,生存期間は中央値に到達していなかった。我が国では再発・難治多発性骨髄腫
MCLに対しては本治療法により 75%の奏効割合と 50%の完全奏効割合が得られた。grade 3,4の好中球減少症が 16%に認められたが,grade 3,4の血小板減少は 3%とわずかであり。非血液毒性は grade 1の嘔気,嘔吐が最大のもので,grade 2以上の非血液毒性は認められなかった。また,Rummelらは,初発進行期 FL,MCLを対象として,R-CHOP対 R-bendamustineのランダム化比較 phase III study を実施し,R-bendamustine が PFSで有意に優れていることを報告し49),我が国でも,初発,
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Fig. 8 Structural formula of bendamustine
Fig. 7 Antitumor response in all evaluable patients. (A) Bestresponses in the 48 patients evaluated by computedtomography scan for change from baseline in the sumof the largest diameter of each target lesion; negativevalues indicate tumor shrinkage. (B) Time on studyfor all 56 patients grouped by histology; bars describethe reason for patient discontinuation.CLL, chronic lymphocytic leukemia; DLBCL, diffuselarge B-cell lymphoma; DLT, dose-limiting toxicity;FL, follicular lymphoma; NHL, non-Hodgkin lympho-ma; MCL, mantle-cell lymphoma; SLL, small lympho-cytic lymphoma; SPD, sum of product of greatestdiameters. (Ref. 44)
進行期高腫瘍量 FL と初発進行期 MCL に対する R-Bendasmustine の phase II study を実施し,bendamus-tineが初発 FL,MCLに対して早期承認されることが期待されている。また,我が国では再発・難治びまん性大
細胞型リンパ腫に対する rituximab+bendamustine併用療法の phase II study を実施した。57 例の再発・難治DLBCL が登録治療され,全奏効割合 62.7%,%CR37.3%と極めて高い有効性と安全性が確認され,再発・難治 DLBCL に対する承認が期待されている50)(Table8B)。2)pralatrextae:葉酸代謝拮抗薬であり,胎児細胞や腫瘍細胞に発現し
*: unconfi rmed CR, **: partial response, ***: stable diseaseEvaluated by the CentraI CT/PET Review Committee and the Central Effi cacy Review Board.1)Indolent B-cell non-Hodgkin lymphoma2)Mantle cell lymphoma
tissue reactivity of four murine monoclonal anti-CD22antibodies. Cell Immunol. 1989, 118: 85-99.
2)DiJoseph J, Armellino DC, Khandke K, et al. CMC-544: aCD22-targeted immunoconjugate of calicheamicin for thetreatment of non-Hodgkin@s lymphoma [abstract]. Eur J Can-cer. 2002; 38 (suppl 7): S150. (http: //dx.doi.org/10.1016/S0959-8049(02)81154-6). Accessed 2013 June 26.
3)DiJoseph JF, Armellino D, Khandke K. CMC-544, an anti-CD22 antibody-targeted calicheamicin therapeutic for the
treatment of B lymphoid malignancies. Blood. 2002, 100:160a.
4)Advani A, Coiffier B, Czuczman MS, et al. Safety, pharmaco-kinetics, and preliminary clinical activity of inotuzumabozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin@s lymphoma: results of a phase I study. JClin Oncol. 2010; 28: 2085-2093.
5)Ogura M, Tobinai K, Hatake K, et al. Phase I study ofinotuzumab ozogamicin (CMC-544) in Japanese patients
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Table 8B Treatment Response to Bendamustine Plus Rituximab in Phase II study(Ref. 50)
Variables
NTumor Response, n(%) ORR, %
[95% CI]CR Rate, %[95% CI]CR PR SD PD NE
5922
(37.3)15
(25.4)10
(16.9)10
(16.9)2
(3.4)62.7
[49.1―75.0]37.3
[25.0―50.9]
Age(P=1.000 with respect to the ORR)
65 years 3714
(37.8)9
(24.3)6
(16.2)7
(18.9)1
(2.7)62.2
[44.8―77.5]37.8
[22.5―55.2]
<65 years 228
(36.4)6
(27.3)4
(18.2)3
(13.6)1
(4.5)63.6
[40.7―82.8]36.4
[17.2―59.3]
Number of prior regimens(P=.027, 1 vs. 2, 1 vs. 3, 2 vs. 3 with respect to the ORR)
1 3816
(42.1)12
(31.6)3
(7.9)5
(13.2)2
(5.3)73.7
[56.9―86.6]42.1
[26.3―59.2]
2 134
(30.8)3
(23.1)4
(30.8)2
(15.4)0
(0.0) 53.8
[25.1―80.8]30.8
[9.1―61.4]
3 82
(25.0)0
(0.0) 3
(37.5)3
(37.5)0
(0.0) 25.0
[3.2―65.1]25.0
[3.2―65.1]
Relapse after ASCT 83
(37.5)2
(25.0)2
(25.0)1
(12.5)0
0.0 62.5
[24.5―91.5]37.5
[8.5―75.5]
Elapsed time since prior treatment(P=.036 with respect to the ORR)
<12 months 90
(0.0) 4
(44.4)1
(11.1)2
(22.2)2
(22.2)44.4
[13.7―78.8]0
[0―33.6]
12 months 2916
(55.2)8
(27.6)2
(6.9)3
(10.3)0
(0.0) 82.8
[64.2―94.2]55.2
[35.7―73.6]
Lactate dehydrogenase(P=.058 with respect to the ORR)
with follicular lymphoma pretreated with rituximab-basedtherapy. Cancer Sci. 2010; 101: 1840-1845.
6)Ogura M, Hatake K, Ando K, et al. Phase I study of anti-CD22 immunoconjugate inotuzumab ozogamicin plus rituxi-mab in relapsed/refractory B-cell non-Hodgkin lymphoma.Cancer Sci. 2012; 103: 933-938.
7)Ogura M, Leach J, Egyed M, et al. Inotuzumab ozogamicin inB-cell non-Hodgkin@ s lymphoma refractory to rituximab+chemotherapy or radioimmunotherapy. JSMO Annual Meet-ing Abstracts. [abstract]. 2012; 23 (suppl 11): xi82-xi98.WS12-6.
8)Ogura M, Uchida T, MacDonald DA, et al. An Open-label,Phase I Study of R-CVP in Combination with InotuzumabOzogamicin in Patients with Relapsed/Refractory CD22-positive B-cell Non-Hodgkin Lymphoma [abstract]. Blood.2011; 118: Abstract3715.
9)Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumabozogamicin, an anti-CD22-calecheamicin conjugate, for re-fractory and relapsed acute lymphocytic leukaemia: a phase 2study. Lancet Oncol. 2012; 13: 403-411.
10)Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chroniclymphocytic leukemia. J Clin Oncol. 2010; 28: 1749-1755.
11)Ogura M, Hatake K, Tobinai K, et al. Phase I Study ofOfatumumab, a Human Anti-CD20 Antibody, in JapanesePatients with Relapsed or Refractory Chronic LymphocyticLeukemia and Small Lymphocytic Lymphoma. Jpn J ClinOncol. 2013; 43: 466-475.
12)Ogura M, Ando K, Ogawa Y, et al. Phase I/II Study of Anti-CD20 Ofatumumab for Relapsed/Refractory B-CLL in Japanand Korea [抄録]. 臨血. 2012; 53: 1063. 抄録番号 OS-1-83.
13)Ogura M, Tobinai K, Hatake K, et al. Phase I study ofobinutuzumab (GA101) in Japanese patients with relapsed orrefractory B-cell non-Hodgkin lymphoma. Cancer Sci. 2013;104: 105-110.
14)Tobinai K, Ogura M, Kobayashi Y, et al. Phase I study ofLY2469298, an Fc-engineered humanized anti-CD20 anti-body, in patients with relapsed or refractory follicular lym-phoma. Cancer Sci. 2011; 102: 432-438.
15)Yoshie O, Fujisawa R, Nakayama T, et al. Frequent ex-pression of CCR4 in adult T-cell leukemia and human T-cellleukemia virus type 1-transformed T cells. Blood. 2002; 99:1505-1511.
16)Ishida T, Utsunomiya A, Iida S, et al. Clinical significance ofCCR4 expression in adult T-cell leukemia/lymphoma: itsclose association with skin involvement and unfavorableoutcome. Clin Cancer Res. 2003; 9: 3625-3634.
17)Ishida T, Inagaki H, Utsunomiya A, et al. CXC chemokinereceptor 3 and CC chemokine receptor 4 expression in T-celland NK-cell lymphomas with special reference to clinicopa-thological significance for peripheral T-cell lymphoma,unspecified. Clin Cancer Res. 2004; 10: 5494-5500.
18)Yamamoto K, Utsunomiya A, Tobinai K, et al. Phase I studyof KW-0761, a defucosylated humanized anti-CCR4 antibody,in relapsed patients with adult T-cell leukemia-lymphoma andperipheral T-cell lymphoma. J Clin Oncol. 2010; 28: 1591-1598.
19)Ishida T, Joh T, Uike N, et al. Defucosylated anti-CCR4monoclonal antibody (KW-0761) for relapsed adult T-cell leu-kemia-lymphoma: a multicenter phase II study. J Clin Oncol.2012; 30: 837-842.
20)Ishida T, Ogura M, Htake K, et al. Multicenter Phase II Studyof Mogamulizumab (KW-0761), a Defucosylated Anti-CCR4Antibody, in Patients with Relapsed Peripheral and Cutane-ous T-Cell Lymphoma [abstract]. Blood. 2012; 120: Ab-stract795.
21)Younes A, Bartlett NL, Leonard JP, et al. Brentuximabvedotin (SGN-35) for relapsed CD30-positive lymphomas. NEngl J Med. 2010; 363: 1812-1821.
22)Younes A, Gopal AK, Smith SE, et al. Results of a pivotalphase II study of brentuximab vedotin for patients withrelapsed or refractory Hodgkin@s lymphoma. J Clin Oncol.2012; 30: 2183-2189.
23)Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplasticlarge-cell lymphoma: results of a phase II study. J Clin Oncol.2012; 30: 2190-2196.
24)Prince HM, Duvic M, Martin A, et al. Phase III placebo-controlled trial of denileukin diftitox for patients withcutaneous T-cell lymphoma. J Clin Oncol. 2010; 28: 1870-1877.
25)O@Connor OA, Wright J, Moskowitz C, et al. Phase II clinicalexperience with the novel proteasome inhibitor bortezomibin patients with indolent non-Hodgkin@s lymphoma andmantle cell lymphoma. J Clin Oncol. 2005; 23: 676-684.
26)Read MA, Neish AS, Luscinskas FW, Palombella VJ, ManiatisT, Collins T. The proteasome pathway is required forcytokine-induced endothelial-leukocyte adhesion moleculeexpression. Immunity. 1995; 2: 493-506.
27)Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter Phase IIStudy of Bortezomib in Patients With Relapsed or RefractoryMantle Cell Lymphoma. J Clin Oncol. 2006; 24: 4867-4874.
28)Hay N, Sonenberg N. Upstream and downstream of mTOR.Genes Dev. 2004; 18: 1926-1945.
29)Bjornsti MA, Houghton PJ. The TOR pathway: A target forcancer therapy. Nat Rev Cancer. 2004; 4: 335-348.
30)Tobinai K, Ogura M, Maruyama D, et al. Phase I study of theoral mammalian target of rapamycin inhibitor everolimus(RAD001) in Japanese patients with relapsed or refractorynon-Hodgkin lymphoma. Int J Hematol. 2010; 92: 563-570
31)Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ.Adenosine-deaminase deficiency in two patients with severe-ly impaired cellular immunity. Lancet. 1972; 2: 1067-1069.
32)Gandhi V, Kilpatrick JM, Plunkett W, et al. A proof-of-
臨 床 血 液 54:10
269(1815)
principle pharmacokinetic, pharmacodynamic, and clinicalstudy with purine nucleoside phosphorylase inhibitorimmucillin-H (BCX-1777, forodesine). Blood. 2005; 106:4253-4260.
33)Ogura M, Tsukasaki K, Nagai H, et al. Phase I study ofBCX1777 (forodesine) in patients with relapsed or refractoryperipheral T/natural killer-cell malignancies. Cancer Sci.2012; 103: 1290-1295.
34)Robertson MJ, Kahl BS, Vose JM, et al. Phase II study ofenzastaurin, a protein kinase C beta inhibitor, in patients withrelapsed or refractory diffuse large B-cell lymphoma. J ClinOncol. 2007; 25: 1741-1746.
35)Richardson PG, Schlossman RL, Weller E et al. Immunomo-dulatory drug CC-5013 overcomes drug resistance and is welltolerated in patients with relapsed multiple myeloma. Blood.2002; 100: 3063-3067.
36)Uike N, Ogura M, Imaizumi Y, et al. Multicenter Phase IDose-Escalation Study of Lenalidomide in Patients withRelapsed Adult T-Cell Leukemia-Lymphoma (ATL) orPeripheral T-Cell Lymphoma (PTCL)[abstract]. Blood. 2012;120: Abstract2737.
37)Fowler NH, Neelapu SS, Hagemeister FB, et al. Lenalidomideand Rituximab for Untreated Indolent Lymphoma: FinalResults of a Phase II Study [abstract]. Blood. 2012; 120:Abstract901.
38)Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, KellyWK. Histone deacetylases and cancer: Causes and therapies.Nat Rev Cancer. 2001; 1: 194-202.
39)Finnin MS, Donigian JR, Cohen A, et al. Structures of ahistone deacetylase homologue bound to the TSA and SAHAinhibitors. Nature. 1999; 401: 188-193.
40)O@ Connor OA, Heaney ML, Schwartz L, et al. Clinicalexperience with intravenous and oral formulations of thenovel histone deacetylase inhibitor suberoylanilide hydroxa-mic acid in patients with advanced hematologic malignancies.J Clin Oncol. 2006; 24: 166-173.
41)Ando K, Ogura M, Suzuki T, et al. A multicenter phase IIstudy of vorinostat in patients (pts) with relapsed or refracto-ry indolent B-cell non-Hodgkin lymphoma (B-NHL) ormantle cell lymphoma (MCL)[abstract]. J Clin Oncol. 2012;30: Abstract8029.
42)Piekarz RL, Frye R, Turner M, et al. Phase II multi-
institutional trial of the histone deacetylase inhibitorromidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009; 27: 5410-5417.
43)Piekarz RL, Frye R, Prince HM, et al. Phase 2 trial ofromidepsin in patients with peripheral T-cell lymphoma.Blood. 2011; 117: 5827-5834.
44)Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosinekinase inhibitor ibrutinib (PCI-32765) has significant activityin patients with relapsed/refractory B-cell malignancies. JClin Oncol. 2013; 31: 88-94.
45)Manfredi MG, Ecsedy JA, Chakravarty A, et al. Characteriza-tion of Alisertib (MLN8237), an Investigational Small-Molecule Inhibitor of Aurora A Kinase Using Novel In VivoPharmacodynamic Assays. Clin Cancer Res. 2011; 17: 7614-7624.
46)Ogura M, Uchida T, Taniwaki M, et al. Phase I andpharmacokinetic study of bendamustine hydrochloride inrelapsed or refractory indolent B-cell non-Hodgkin lympho-ma and mantle cell lymphoma. Cancer Sci. 2010; 101: 2054-2058.
47)Ohmachi K, Ando K, Ogura M, et al. Multicenter phase IIstudy of bendamustine for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Can-cer Sci. 2010; 101: 2059-2064.
48)Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plusrituximab is effective and has a favorable toxicity profile inthe treatment of mantle cell and low-grade non-Hodgkin@ slymphoma. J Clin Oncol. 2005; 23: 3383-3389.
49)Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamus-tine plus rituximab versus CHOP plus rituximab as first-linetreatment for patients with indolent and mantle-cell lympho-mas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013; 381: 1203-1210.
50)Ogura M, Ando K, Niitsu N, et al. A multicenter phase IIstudy of bendamustine with rituximab in patients withrelapsed/refractory diffuse large B-cell lymphoma (DLBCL)[abstract]. J Clin Oncol. 2012; 30: Abstract8023.
51)O@Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in pa-tients with relapsed or refractory peripheral T-cell lympho-ma: results from the pivotal PROPEL study. J Clin Oncol.2011; 29: 1182-1189.