Bischof Delaloye, A.

Buchegger, F.

Ketterer, N.

Larson, S. M.

Mach, J.-P

Press, O. W.

Prior, J. O.

RERO DOC Digital Library

Improving the chance of cureof follicular lymphoma bycombining immunotherapyand radioimmunotherapy basedon anti-CD20 antibodies?The recently published ESMO lymphoma treatment guidelines[1] recommend the use of single-agent rituximab as an optionin follicular lymphoma (FL) for avoiding the side-effects ofchemotherapy. We may add to this point that results from theliterature as well as our own observation show that radiolabeledanti-CD20 radioimmunotherapy (RIT), as a treatmentconsisting of two injections given at a 7-day interval, can leadto high rates of complete responses (CRs) and over 10 yearsrecurrence-free survival in a signiﬁcant percentage of patients.These results, conﬁrmed at the molecular level in a highpercentage of cases, were observed with treatment at ﬁrst line,in consolidation and in relapsed/refractory indolent lymphoma[2–4]. They favorably compare with the above-mentionedresults of single-agent rituximab [1] shown to induce long-termremissions of FL and to represent a well-tolerated maintenancetherapy [5].Surprisingly, these two very efﬁcient forms of B cell-speciﬁcanti-CD20-mediated therapies have never been tested incombination in a well-designed clinical trial of FL. In the mostrecent randomized, phase III trial of untreated FL, RIT, andrituximab treatments were compared, but they were bothassociated with the same combination of cyclophosphamide,doxorubicin, vincristine and prednisone (CHOP)chemotherapy [6]. The two arms gave excellent and similarresults, but the two antibody-mediated therapies could not beevaluated individually or in combination.The combination of these two forms of anti-CD20immunotherapies might increase the CR with less side-effectsthan chemotherapy and preserve the T cells’ immune defenses.Indeed, the positive role of T cells’ responses againstlymphomas has been well documented in experimental andclinical investigations, including idiotype vaccination andallogeneic bone marrow transplantation [7]. Furthermore, thefact that the two approved anti-CD20 antibodies,tositumomab and ibritumomab, are of murine origin includestumor targeting of new antigens, which can be recognized intheir processed form by the patient’s T lymphocytes [8]. Theimportant role of effector cells from innate immunity, such asnatural killer (NK) cells, is well known both for antibody-dependent cell mediated cytotoxicity and for the preventionof recurrence. Interestingly, it was recently shown thatinjection of rituximab resulted in the activation of the NKcells in patients with the high-afﬁnity Fcγ receptor geneticpolymorphism [9].The strong efﬁcacy of RIT cannot be entirely explained bythe relatively low radiation dose to the tumor cells or by theassociated administration of unlabeled anti-CD20 antibody,but probably by the combination of both that associate withthe patient’s preserved T cells immunity. It has been recentlyreported that irradiated lymphoma cells have an increasedimmunogenicity and that irradiation of lymphoma,accompanied by systemic delivery of a TLR7 agonist, caninduce durable antitumor immune response in murinesyngeneic lymphoma models [10].In conclusion, we think that in FL the combination of thesetwo antibody-mediated biotherapies might produce a synergyleading to higher CRs and longer disease-free survival ratesthan each single modality and, thanks to the preservation ofthe patient’s immune system, improve the chance of cure.F. Buchegger1,2*, J.-P. Mach3, O. W. Press4, A. BischofDelaloye5, S. M. Larson6, J. O. Prior1 & N. Ketterer71Department of Nuclear Medicine, Lausanne University Hospital,Lausanne2Department of Nuclear Medicine, Geneva University Hospitals, Geneva3Department of Biochemistry, University of Lausanne, Lausanne,Switzerland4Department of Medical Oncology, University of Washington MedicalCenter, Seattle, USA5Faculty of Medicine, University of Lausanne, Lausanne, Switzerland6Department of Radiology, Memorial Sloan Kettering Cancer Center,New York, USA7Clinic Bois-Cerf, Onco-Hematology, Lausanne, Switzerland(*E-mail: franz.buchegger@chuv.ch)disclosureThe institution of OWP receives research funding from Roche/Genentech for clinical trials for which he is PrincipalInvestigator (PI). He owns a minor amount of stock inEmergent Biosolutions. ABD is an occasional scientiﬁc advisorof Spectrum Pharmaceuticals. The other authors do not declareany conﬂict of interest.references1. Ghielmini M, Vitolo U, Kimby E et al. ESMO Guidelines consensus conference onmalignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL),follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Ann Oncol2013; 24: 561–576.letterstotheeditorletters to the editor Annals of Oncology 24: 1948–1950, 2013© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oup.com.2. Kaminski MS, Tuck M, Estes J et al. 131I-tositumomab therapy as initialtreatment for follicular lymphoma. N Engl J Med 2005; 352: 441–449.3. Goff L, Summers K, Iqbal S et al. Quantitative PCR analysis for Bcl-2/IgH in aphase III study of Yttrium-90 ibritumomab tiuxetan as consolidation of ﬁrstremission in patients with follicular lymphoma. J Clin Oncol 2009; 27:6094–6100.4. Buchegger F, Antonescu C, Helg C et al. 6 of 12 relapsed refractory indolentlymphoma patients treated 10 years ago with 131I-tositumomab remain incomplete remission. J Nucl Med 2011; 52: 896–890.5. Martinelli G, Schmitz SF, Utiger U et al. Long-term follow-up of patients withfollicular lymphoma receiving single-agent rituximab at two different schedules intrial SAKK 35/98. J Clin Oncol 2010; 28: 4480–4484.6. Press OW, Unger JM, Rimsza LM et al. Phase III randomized intergroup trial ofCHOP plus rituximab compared with CHOP chemotherapy plus 131Iodine-tositumomab for previously untreated follicular non-Hodgkin Lymphoma: SWOGS0016. J Clin Oncol 2013; 31: 314–320.7. Khouri IF, Saliba RM, Erwin WD et al. Nonmyeloablative allogeneictransplantation with or without 90yttrium ibritumomab tiuxetan is potentiallycurative for relapsed follicular lymphoma: 12-year results. Blood 2012; 119:6373–6378.8. Lanzavecchia A, Abrignani S, Scheidegger D et al. Antibodies as antigens. Theuse of mouse monoclonal antibodies to focus human T cells against selectedtargets. J Exp Med 1988; 167: 345–352.9. Veeramani S, Wang SY, Dahle C et al. Rituximab infusion induces NK activationin lymphoma patients with the high-afﬁnity CD16 polymorphism. Blood 2011;118: 3347–3349.10. Dovedi SJ, Melis MH, Wilkinson RW et al. Systemic delivery of a TLR7 agonist incombination with radiation primes durable antitumor immune responses inmouse models of lymphoma. Blood 2013; 121: 251–259.doi: 10.1093/annonc/mdt198Published online 23 May 2013Spin and bias: the tip of theicebergVera-Badillo et al. [1] have to be congratulated for uncoveringa problem with reporting of trial results, a problem thatdistorts the record, impedes inference, and can lead to ﬂawedmedical decisions. It is important to note that the associatedproblems of biased reporting and spin remain problems nomatter how often they occur; once is once too often.Hence, the proportions presented should be understood inthis context, and we should not lose sight of the forest for thetrees. Nevertheless, I would propose that the proportionspresented should have been based on the subset of 30 trialswith complete information (including the primary end pointthat was prospectively speciﬁed), either instead of or inaddition to the proportions that were presented based on thefull sample of 164 trials.We are told, for example, that 7 of the 30 trials reported adifferent primary end point, and we can only imagine that thisswitch would have occurred in a higher proportion of the other134 trials, given that the authors of those trials did not need toworry about getting caught. This uncertainty undermines ourability to offer credible statements about how often these 134trials were biased or spun. But we do see bias in at least 7 ofthe 30, and have to wonder how often there was bias and/orspin in the other 23 among these 30. This would be a rathertelling statistic, arguably more telling than the one based onthe full set of 164.Moreover, the problems reported, though certainly ofsubstantial importance, may still represent only the tip of theiceberg, and not only because we can check for changes in theprimary end point in only 30 of the 164 trials. Beyond this, wealso have the fact that there are many more biases, far toomany to list here, that may have gone into producing spuriousstatistical signiﬁcance in the primary end point. So what wehave here is a best-case scenario, and a comprehensive look atspin, plus bias as deﬁned here, plus bias deﬁned more broadly,might reveal a far worse state of affairs in the trial researchrecord [2].V. W. Berger*Biometry Research Group, National Cancer Institute, and UMBC,Bethesda, USA(*E-mail: vb78c@nih.gov).fundingThis research received no speciﬁc grant from any fundingagency in the public, commercial, or not-for-proﬁt sectors.disclosureThe author has declared no conﬂict of interest.references1. Vera-Badillo FE, Shapiro R, Ocana A et al. Bias in the reporting of end pointsof efﬁcacy and toxicity in randomized, clinical trials for women with breast cancer.Ann Oncol 2013; 24: 1238–1244.2. Berger VW, Palys K. Medical Research: What Is Wrong with This Picture? TheInternational Journal of Person Centered Medicine 2012; 2: 707–715.doi: 10.1093/annonc/mdt189Published online 23 May 2013Spin and bias: the tip of theicebergWe thank Dr Berger for his kind comments on our study[1]. Our primary aim was to determine the frequency ofspin and bias applied to misreporting the primary endpoint, and failure to include a description of toxicity in theabstract. To focus the ﬁndings of our research on only 30trials with complete reporting of the primary end point(only 18% of the total sample) would perhaps have allowedus to separate spin (i.e. where complete information isprovided but results are presented in such a way as tomake them appear to be more favourable to theAnnals of Oncology letters to the editorPublished by Oxford University Press on behalf of the European Society for Medical Oncology 2013.This work is written by a US Government employee and is in the public domain in the US.Volume 24 | No. 7 | July 2013 letters to the editor | 

Improving the chance of cure of follicular lymphoma by combining immunotherapy and radioimmunotherapy based on anti-CD20 antibodies?

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library