Improving the Care of Your Patient with NHL - Educational Concepts ...

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Improving the Care of Your Patient with NHL - Educational Concepts ...

A lkylating agentsB endamustineC HOPD oxorubicinEF ludarabineG aliximabH igh dose therapyI nterferonJKL enalidomideM abTheraN ovantroneO fatumumabP rednisoneQR adiationS plenectomyT emsirolimusUV elcadeW atch & WaitXYZ evalin, Bexxar


Standard of care in pts with indolent lymphomas‣ Combined Immuno-Chemotherapy is the standard of care‣ R-chemotherapy plus R-maintenance appears asthe optimal option for patients with relapsed disease‣ Which chemotherapy in combination with Rituximab? Chlorambucil-based (MCP), F-based (FCM), CHOP-like, CVP Role of bendamustine has been recently investigated in this setting‣ Open question: R-maintenance after 1st-line R-containing regimens? PRIMA study addresses this question StiL NHL 7-2008 study proves duration of maintenance R after B-R SAKK study proves duration of maintenance after RMJR


Watch & wait or early treatment ?Is there a need for immediate treatment in asymptomaticpatients with advanced indolent / follicular lymphomasor can a watch and wait strategy being considered?


Watch & wait or early treatment?Ardeshna KM et al. Watch & wait versus immediate systemic treatment. Lancet 262: 516, 2003Watchful waiting versus Chlorambucil 10 mg daily contin.prospective randomized, n = 309, recruitement phase 1981-1990Survival watch & wait immediate treatment5 years 58 % 57 %10 years 34 % 35 %15 years 22 % 21 %Median 6,7 years 5,9 years


Watch & wait or early treatment ?Overall survivalDisease-associated survivalArdeshna KM et al. Lancet 262: 516, 2003


Watch & wait or early treatment ?Ardeshna KM et al. Lancet 262: 516, 2003MJR


Watch & wait or early treatment ?Watch & wait:time to first treatmentMedian time to first treatment: 2,6 yearsActuarial chance of not needingchemotherapy at 10 yrs was 19%and 40% in patients older than 70 yearsArdeshna KM et al. Lancet 262: 516, 2003MJR


Indications for treatment in indolent lymphomasStages I, II, limited III (up to 5 involved lymph node regions): curative intention?Disease associated symptoms (B-symptoms)Hematopoetic insufficiency: anemia, granulocytopenia, thrombocytopeniaRapid tumor progression: doubling of manifestations within 1 yearBulky disease (> 6 cm diameter)Autoimmune phenomens, such as AIHA or ITPHypogammaglobulinemia with recurrent infectionsHyperviskosity syndrome by monoclonal paraproteinemiaMJR


Myeloablative Therapy with Subsequent ASCTin First Remission of Follicular LymphomaTrial Induction Consolidation EFS p OS (%) pLenz et al CHOP/MCP TBI/Cyclo 5-yr PFS 0.0001 n. a.GLSG ASCT (n=153) 65 %Phase III IFN (n=154) 33 %Deconinck VCAP TBI/Cyclo 5-yr EFS 0.050 5-year 0.49GOELAMS ASCT (n=86) 60 % 78Phase III CHVP/IFN IFN (n=80) 48 % 84Sebban CHOP TBI/Cyclo/VP16 7-yr EFS 0.11 7-year 0.53GELA ASCT (n=192) 38 % 78Phase III CHVP/IFN IFN (n=209) 28 % 71Lenz et al, J Clin Oncol, 22: 4926, 2004. Deconninck et al, Blood, 105: 3817, 2005. Sebban et al, Blood, 108: 2540, 2006.


Follicular lymphomaCHVP + IFN 209CHOP + auHSCT 192Sebban. Blood, 2006;108:2540


CHVP + IFN 209CHOP + auHSCT 192Sebban. Blood, 2006;108:2540


Treatment SchedulesR-HDShd-VP16hd-CyMITO/L-PAM+ Autograft2 APO+2 DHAPRituximabRituximabP B P CharvestRituximabdaysG-CSFG-CSFG-CSF0 120 180 230 300140CHOP-RCHOP 1-3 CHOP 4-6RituximabMarco Ladetto et al.:RANDOMIZED GITMO/IIL TRIALCHOP+R vs. HIGH-DOSE THERAPY+R (R-HDS) INHIGH RISK FOLLICULAR LYMPHOMA (FL). ASH 2007


R-HDS vs CHOP-R RANDOMIZED TRIALEVALUABLE PATIENTS: 134PFS ACCORDING TO TREATMENT ARMMedian follow up: 51 monthsR-HDS vs CHOP-R68% at 4 yrs.CHOP-RR-HDSp


R-HDS vs CHOP-R RANDOMIZED TRIALEVALUABLE PATIENTS: 134OS ACCORDING TO TREATMENT ARMR-HDS vs CHOP-RMedian follow up: 51 months81% at 4 yrs.80% at 4 yrs.P=NS


ASCT in follicular lymphomasASCT is an appropriate treatment choice for younger patientswith chemosensitive recurrent follicular lymphomaASCT remains investigational in the initial treatment offollicular lymphoma‣ No demonstrated overall survival benefit‣ Possible improvement in overall survival by addingRituximab in treatment strategies‣ Increase of 2nd malignanciesASH, 2005MJR


Does combined immunochemotherapywith rituxan improveoverall survival in patients withindolent non-hodgkin’s lymphomacompared to chemotherapy alone?A Meta-AnalysisHolger Schulz, Nicole Skoetz, Julia F. Bohlius,Sven Trelle, Alexander Greb, Thilo Koberand Andreas EngertCochrane ReviewCochrane Haematological Malignancies Group (CHMG)Internal Medicine I, University of Cologne. www.CHMG.de Schulz, et al. J Natl Cancer Inst 2007;99:1-9


Combined Immunochemotherapy with Rituximab Improves Overall Survivalin Patients with Follicular and Mantle Cell Lymphoma: Updated Meta-AnalysisHolger Schulz, Andreas Engert et al. Cochrane Hematological Malignacies Group (CHMG)‣ Six randomised, controlled trials comparing rituximab plus chemotherapy withchemotherapy alone in indolent and mantle cell lymphoma were identified R-CHOP vs CHOP (x2) R-CVP vs CVP R-FCM vs FCM R-MCP vs MCP R-CNOP vs CNOP‣ Survival meta-analysis performed on untreated patients(7 trials; n=1.943, 5 published, 2 abstract form)Schulz, et al. J Natl Cancer Inst 2007;99:1-9


Overall survival:Meta-Analysis Total GroupStudy HR [95%-CI] Weight [%] HR [95%-CI]Lenz 2005 4.11Baez 2005 6.900.96Forstpointner 2005 15.10Marcus 2005 16.100.70Hiddemann 2005 28.860.60Herold 2005 28.920.600.960.42Total (95% CI) 100.00 0.62 (0.49 - 0.77)0.2 0.5 1 2Favors R + Chemo Favors ChemoTotal events: 100/760 143/718Test for heterogeneity: (P = 0.60), I² = 0%Schulz, et al. J Natl Cancer Inst 2007;99:1-9


Intergroup phase III trial: study designRANDOMIZEDCHOP every21 daysmaximum 6 cyclesRituximab + CHOPevery21 daysmaximum 6 cyclesCRPRRANDOMIZEDObservationRituximabmaintenance*Van Oers MHJ, et al. Abstract, ASH 2005*375mg/m 2 every 3 monthsfor 2 years or until relapse


1009080706050403020100Intergroup phase III trialProgression free survivalProgression free survival from 2nd randomizationOverall Logrank test: p


EORTC 20981 - van OersAbstr. ASH 2005 (Maint 1 x R, q 3 mo, up to 2 yrsInduction n=465, Maint n=334, med. foll. up 33 monthsobservationmaintenanceRituximabPFS* (months) 15.0 51.6 p < 0.0001after CHOP 11.6 42after CHOP-R 23.1 52 p = 0.004after CR 14.5 51.6after PR 15.6 45.4OS (3 years) 77.1% 85.1% p = 0.011 *** after 2nd randomization ** HR = 0.52MJR


EORTC 20981 - van OersAbstr. ASH 2005 (Maint 1 x R, q 3 mo, up to 2 yrsInduction n=465, Maint n=334, med. foll. up 33 monthsobservationmaintenanceRituximabPFS* (months) 15.0 51.6 p < 0.0001after CHOP 11.6 42after CHOP-R 23.1 52 p = 0.004after CR 14.5 51.6after PR 15.6 45.4OS (3 years) 77.1% 85.1% p = 0.011 *** after 2nd randomization ** HR = 0.52MJR


Adverse events - EORTC 20981 van OersObservationRituximabGrade 3 Grade 4 Grade 3 Grade 4Leukocytopenia 2,4% 1,8% 6,0% 0,6%Granulocytopenia 3,6% 1,8% 6,6% 4,2%Infections 1,8% 0,6% 7,2% 1,8%Cardial 4,2% 4,2% 1,8%Pulmonary 1,2% 1,2%Skin 0,6% 2,4%MJR


1009080706050403020100Intergroup phase III trialOverall survivalOverall survival from 2nd randomizationOverall Logrank test: p=0.011Hazard ratio: 0.52from 2nd randomizationR-maintenance3 yrs 85.1 %observation3 yrs 77.1 %0 1 2 3 4 5 6(years)O N Number of patients at risk : Treatment39 167 148 99 50 14 2 Observation23 167 155 112 69 19 4Mabthera


Standard of care in pts with indolent lymphomas‣ There is still a role for watch & wait in asymptomatic patients‣ Combined Immuno-Chemotherapy is the standard of care‣ R-chemotherapy plus R-maintenance appears asthe optimal strategy for patients with relapsed disease‣ Which chemotherapy in combination with Rituximab? Chlorambucil-based (MCP), F-based (FCM), CHOP-like, CVP Role of bendamustine has been recently investigated (ASH 2009)‣ R-maintenance after 1st-line R-containing regimens? PRIMA study addresses this question StiL NHL 7-2008 study proves duration of maintenance SAKK study proves duration of maintenance after RMJR


Challenging the standard in indolent lymphoma‣ Combined Immuno-Chemotherapy is the standard of care‣ Which chemotherapy in combination with Rituximab? CHOP, CVP, F or FCM, MCP, R alone, or … ??Doctor´s choice in the FIT trialLymphoCare Study(induction before Zevalin cons.) (Friedberg et al, JCO 2009)First-line Regime % %- Chlorambucil 10- CVP / COP 27 CVP-R 23- CHOP or CHOP-like 43 CHOP-R 55- Fludarabine-combination 5 Fludarabine-R 15MJR


Bendamustine plus Rituximab versus CHOP plus Rituximab in the First-LineTreatment of Patients with Indolent and Mantle Cell Lymphoma –Final Results of a Randomized Phase III Study of theStiL (Study Group indolent Lymphomas, Germany)Mathias J. Rummel, N. Niederle, G. Maschmeyer, G. A. Banat, U. von Grünhagen,C. Losem, G. Heil, M. Welslau, C. Balser, U. Kaiser, H. Ballo, E. Weidmann,H. Dürk, D. Kofahl-Krause, F. Roller, J. Barth, D. Hoelzer, A. Hinke,and W. Brugger .on behalf of the StiL .Blood 114: 168 (abstr #405), 2009


Bendamustine-Rituximab (B-R) vs CHOP-RStiL NHL 1-2003Bendamustine-RituximabFollicularWaldenströmsMarginal zoneSmall lymphocyticMantle cellRCHOP-RituximabBendamustine 90 mg/m 2 day 1+2 + R day 1, max 6 cycles, q 4 wks.CHOP-R, max 6 cycles, q 3 wks.


Defined Indications for treatmentB-symptomsHematopoietic failure(Hb < 11 g/dl, granulocytes < 1.500 /µl, thrombocytes < 100.000 /µl)Large tumor burden(3 areas > 5 cm or 1 area > 7.5 cm)Rapid progression(increase of tumor mass > 50% within 6 months)Complications due to disease(pain, infarction of spleen, hyperviscosity syndrome, etc.)MJR


Entities549 patients randomized. 513 patients evaluable for response and toxicityB-R CHOP-R Age (median)Total n 260 253 64Follicular 54 % 139 140 60Mantle cell 18 % 45 48 70Marginal zone 13 % 37 30 66Waldenströms 8 % 22 19 64SLL 4 % 10 11 68Unclassifiable 2 % 7 5 69MJR


Patient characteristicsB-R(n=260)CHOP-R(n=253)Age (median) 64 yrs 63 yrs> 70 yrs. 23 % 23 %Stage IV 77 % 77 %Bone marrow 68 % 67 %B-Symptoms 38 % 29 %LDH > 240 U/l 38 % 34 %Bulky disease 27 % 29 %IPI > 2 37 % 34 %FLIPI 0-1 12 % 19 %FLIPI 2 n = 27942 % 33 %FLIPI > 3 46 % 48 %MJR


B-R vs CHOP-R - Hematotoxicity grades 3+4B-R (n=1.450)CHOP-R (n=1.408)(% of cycles) (% of cycles) P valueLeukocytopenia 12,1 38,2 < 0.0001Neutropenia 10,7 46,5 < 0.0001G-CSF administered 4,0 20,0 < 0.0001Thrombocytopenia 0,7 1,2Anemia 1,4 1,9


B-R vs CHOP-R - Toxicities(all CTC-grades)B-R (n=260)CHOP-R (n=253)(no. of pts) (no. of pts) P valueAlopecia - +++ < 0.0001Paresthesias 18 73 < 0.0001Stomatitis 16 47 < 0.0001Skin (erythema) 42 23 = 0.0122Allergic reaction (skin) 40 15 = 0.0003Infectious complications 96 127 = 0.0025- Sepsis 1 8 = 0.0190


Dose reductionB-RCHOP-R(n = 1.450) (n = 1.408)Cycles applied (average) 5,58 5,57Full dose received (% of cycles) 96,1 % 88,8 %Only dose reduction of chemotherapy, Rituximab dose reduction was not countedIn 24 CHOP-R pts vincristine was discontinued during the treatment due to neuropathy


ResultsResponse ratesB-RCHOP-R(n=260) (n=253) P valueORR 92,7 % 91,3 %CR 39,6 % 30,0 % = 0.0262SD 2,7 % 3,6 %PD 3,5 % 2,8 %MJR


Progression free survivalB-R: 54,9 vs CHOP-R: 34,8 months (median)Probability1.00.90.80.70.60.50.40.30.20.1HR = 0.57 (95% CI: 0.43 - 0.76)p = 0.00012B-RCHOP-R0.00 12 24 36 48 60 72 monthsMedian observation period 34 monthsMJR


Time To Next Treatment1.00.90.8B-R: not reached vs CHOP-R: 37,5 months (median)HR = 0.52 (95% CI: 0.38 - 0.70)p = 0.00002Probability0.70.60.50.40.30.20.10.0B-RCHOP-R0 12 24 36 48 60 72 84 monthsMJR


Progression free survivalfollicular lymphomaB-R: not reached vs CHOP-R: 46,7 months (median)Probability1.00.90.80.70.60.50.40.30.20.1HR = 0.63 (95% CI: 0.42 - 0.95)p = 0.0281B-RCHOP-R0.00 12 24 36 48 60 72 monthsMJR


Progression free survivalsubentities1.00.90.80.70.60.50.40.30.20.10.0Follicularp = 0,02810 12 24 36 48 60 72B-RCHOP-R1.00.90.80.70.60.50.40.30.20.10.0CHOP-RMantle cellp = 0,0146B-R0 12 24 36 48 60 721.00.90.80.70.60.50.40.30.20.10.0Marginal zonep = 0.6210B-RCHOP-R0 12 24 36 48 60 721.00.90.80.70.60.50.40.30.20.10.0p = 0.0024WaldenströmB-RCHOP-R0 12 24 36 48 60 72MJR


PFS of Complete RemissionsB-R vs CHOP-R1.00.9p = 0.1779Probability0.80.70.60.50.40.30.20.10.0B-RCHOP-R0 12 24 36 48 60 72 monthsMJR


PFS of Partial RemissionsB-R vs CHOP-R1.00.9p < 0.0001Probability0.80.70.60.50.40.30.20.10.0B-RCHOP-R0 12 24 36 48 60 72 monthsMJR


PFS of CR vs PRB-R1.00.90.8p = 0.64340.7Probability0.60.5PRCR0.40.30.20.10.00 12 24 36 48 60 72 monthsMJR


PFS of CR vs PRCHOP-R1.00.90.8p = 0.00740.7Probability0.60.50.40.30.20.10.0PRCR0 12 24 36 48 60 72 monthsMJR


PFS for LDH normalB-R vs CHOP-R1.00.90.8p < 0.0001Probability0.70.60.50.40.30.20.10.0B-RCHOP-R0 12 24 36 48 60 72 monthsMJR


PFS for LDH > 240 U/lB-R vs CHOP-R1.00.90.8p = 0.3134Probability0.70.60.50.4B-R0.30.2CHOP-R0.10.00 12 24 36 48 60 72 monthsMJR


Peripheral Blood Stem Cell Mobilization after Bendamustinecontaining Chemotherapy in indolent LymphomasNo data about capacity of peripheral blood stem cell mobilizationor a possible stem cell toxicity of BendamustineOne in vitro study demonstrated a lower stem cell toxicity ofBendamustine than of fludarabine 1‣ Clinically relevant, if patients treated with Bendamustine are ableto mobilize enough stem cells (> 2.0 x 10 6 cells/kg) for subsequenthigh dose therapy with autologous stem cell support1. Schmidt-Hieber et al. Bendamustine, but not fludarabine, exhibits a low stem cell toxicity invitro. J Canc Res Clin Oncol; 135: 227-34, 2009.MJR


Results CD34 yieldB-R vs CHOP-RB-RCHOP-RAge (yrs, median) 51 53Mobilization performed 23 23- directly after induction 18 18- at later relapse 5 5Endoxan + G-CSF 10 10G-CSF steady state 7 3CD34+ /kg x 10 6 4,55 6,17Number of apheresis 1,85 1,66No of pts with


B-R vs CHOP-R - SAE and secondary malignanciesB-R (n=260)CHOP-R (n=253)SAE reports 49 742nd.-NPL 15 20- Prostate 2 4- Colon/gastric 4 4- Bronchial 1 2- Kidney / urothel 3 1- Pancreatic - 2- Other carcinoma 4 6- MDS 1 -- AML - 1


Bendamustine-R vs CHOP-RSummary‣ Randomized trial included 513 evaluable patients‣ B-R significantly improved PFS and CR rates compared to CHOP-Rin patients with FL, MCL and Waldenström`s macroglobulinemia‣ B-R shows a better tolerability profile compared to CHOP-R with- no alopecia- less hematotoxicity, G-CSF used, infections, and neuropathy


Bendamustine-R vs CHOP-RConclusionBendamustine plus Rituximab has the potentialto become a treatment of 1 st -choice in these disease entities


Bendamustine-Rituximab + 2 vs 4 yrs RituximabStiL NHL 7-2008 - MAINTAINBendamustine-Rituximab+ 2 years Rituximabq 2 monthsFollicular LymphomaRBendamustine-Rituximab+ 4 years Rituximabq 2 months


B-R + Watch & Wait vs B-R + 2 years RituximabStiL NHL 7-2008 - MAINTAINWaldenströmsMarginal zoneMantle cell(for mantle cell not eligible for APBSCT)RBendamustine-Rituximab+ Watch & WaitBendamustine-Rituximab+ 2 years Rituximabq 2 months


Durable response after lenalidomide oralmonotherapy in patients with relapsed orrefractory DLBCL, MCL, FL III, T-NHL:Results on an international study (NHL-003)ASH 2009, Abstract # 1676T. E. Witzig, J. M. Vose, P.L. Zinzani, C. B. Reeder, R. Buckstein, J.Polikoff , P. Guo; D. Pietronigro, A. Ervin-Haynes,M. S. Czuczman


PatientsLenalidomide 25mg/d d 1-21/ q28Continuously until progress or intolerable toxicityTotal N= 217 %Median Age 69 (21-87)DLBCL 108 50MCL 57 26FL-III 19 9TL 33 15Median time since diagnosis(years)Median no of prior therapiesn (range)Rituximab pretreated,n (%)2,7 (0,04 – 20,6)3 (1-13)94 (205/217)Witzig et al, ASH 2009, # 1676


ResultsnORRCR / CruMedian PFSMedian RD%%Total 217 35 13 3,7 10,6DLBCL 108 28 7 2,7 4,6MCL 57 42 21 5,7 n.r.FL-III 19 42 2 8,9 n.r.TL 33 45 7 5,4 12,8Witzig et al., ASH 2009, # 1676


A Biologic Combination of Lenalidomide and Rituximabfor Front-Line Therapy of Indolent B-Cell NHLNathan Fowler, Peter Mclaughlin, Fredrick Hagemeister, Larry W.Kwak, Michelle Fanale, Sattva Neelapu, Luis Fayad, Barbara Pro,Crystal Sergent, Shana White, Felipe SamaniegoDepartment of Lymphoma/Myeloma, MD Anderson Cancer Center,Houston, TexasASH 2009, Abstract # 1714


Study DesignDrug Dose AdministrationRituximab 375 mg/m2 iv Day 1Lenalidomide 20 mg/day oral Day 1-21• 28 day cycle, with delay for toxicity or cytopenia• Restaging after 3, and 6 cycles.• Lenalidomide increased to 25 mg/day after 3 cycles if SD.


Response Lenalidomid + RituximabCharacteristic (#N) SD PR CR/Cru ORR (CR/CRu)Follicular (17) 1 0 16 94% (94%)SLL (3) 0 2 1 100% (33%)Marginal Zone/MALT (8) 3 1 4 63% (50 %)Total (28) 4 3 21 86% (75%)


Phase 2 VERTICAL study in relapsed or refractoryfollicular lymphoma: Study designCycle 1Cycles 2–4Days 1 2 8 15 2235R: rituximabB: bendamustineV: bortezomibDays 1 2 8 15 2235• Patients received five 35-day treatment cycles• When given on the same day, the order of administration was V→B→R• Concomitant medications included:• Antidiarrheal agents, anti-emetics and prophylactic acetaminophen and diphenhydramine forrituximab infusionsFowler et al. ASH 2009 (Abstract 933) – data from oral presentation


Bendamustine Rituximab plus BortezomibversusBendamustine plus Rituximab (B-R)In relapsed follicular lymphomaand Waldenströms diseaseNHL 8 - 2010MJR


Bo-B-R + 2 years R vs B-R + 2 years RRandomized Phase III StudyFollicularWaldenströmMarginal zoneRBortezomib - B-R (V-BR)q 4 wks+ 2 years R, q 3 monthsV 1,6 mg/qm, 1, 8, 15, q 29 dB-Rq 4 wks+ 2 years R, q 3 months


OfatumumabCompared to Rituximab similar antibody-dependent cellularcytotoxicity stronger complement-dependentcytotoxicity, and that even to lymphoma cells with low CD20antigen density in vitro superior in inducing lysis in differentB-cell lines (SU-DHL-4, Daudia, and Raji) active in B-CLL cells resistant to rituximab1Teeling JL, et al. Blood. 2004;104(6):1793-1800.2Teeling JL, et al. J Immunol. 2006;177(1):362-371.


Ofatumumab in Rituximab-refractory follicular NHL‣ Grade 1 or 2 refractory to rituximab alone or in comb. with chemotherapy‣ 116 patients. 8 weekly doses of 500 mg or 1.000 mg‣ Overall response rate 11 % (1.000 mg ORR 10%)‣ PFS and RD was 6.0 monthsAbstract at ASH 2009, Hagenbeek et al.


Ofatumomab plus Bendamustine vs BendamustineDose schedule for the final protocolOfatumumab plusBendamustine 90 mg/m 2q 3 weeksIndolent NHLRBendamustine 120 mg/m 2q 3 weeks


Standard of care in pts with indolent lymphomas‣ There is still a role for watch & wait, despite new therapy modalities‣ Combined Immuno-Chemotherapy is the standard of care‣ R-chemotherapy plus R-maintenance appears asthe optimal option for patients with relapsed disease‣ A study of 513 randomized pts shows that Bendamustine-R is superiorto CHOP-R in regard of efficacy while being associated with less toxicity‣ Bendamustine plus Rituximab has the potentialto become a treatment of 1 st -choice in these disease entities‣ Open questions: R-maintenance after 1st-line R-containing regimens PRIMA study was reported to be positive, results ASCO 2010 SAKK study proves duration of maintenance after R-monotherapy StiL NHL 7-2008 study proves duration of maintenance R after B-R‣ Role of Lenalidomide, Bortezomib and Ofatumumab has to be defined


Improving the care of patientswith indolent lymphomaMathias J. RummelMed. Klinik IV/ V - HämatologieKlinikum der Justus-Liebig-Universität Gießen

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