IntroduÃÃo: A Leucemia LinfocÃtica CrÃnica (LLC) à uma neoplasia caracterizada pela proliferaÃÃo clonal de linfÃcitos de aspecto maduro. Apresenta curso clÃnico e prognÃstico heterogÃneo. Rai e Binet criaram sistemas de prognÃsticos clÃnicos que classificam a LLC em baixo, intermediÃrio e alto risco. Surgiram os marcadores biolÃgicos de prognÃstico que aumentaram o poder preditivo na LLC. Objetivo:Caracterizar os marcadores clÃnicos e biolÃgicos de pognÃstico dos pacientes com LLC do ambulatÃrio do Hospital UniversitÃrio Walter CantÃdio (HUWC)/Centro de Hematologia e Hemoterapia do CearÃ/HEMOCE. Metodologia: Trata-se de um estudo retrospectivo, transversal e observacional com 43 pacientes portadores de LLC, recrutados de forma randomisada, no perÃodo de agosto de 2007 a Junho de 2009. Foram coletados dos pacientes dados nos prontuÃrios, entrevista e trÃs amostras com 5,0 ml de sangue venoso perifÃrico em Ãcido etilenodiaminotetraacÃtico (EDTA) para o hemograma, por metodologia automatizada no equipamento CellDynÂ, modelo 3.500; dosagem da Ã2-microglobulina (Ã2-M) sÃrica pelo teste quantitativo automatizado no aparelho MINI- VIDAS (BioMÃrieuxÂ) e imunofenotipagem em citÃmetro de fluxo Beckman Coulter EPICS XL-MCL (Coulter). Em seguida, foi coletado pela punÃÃo da medula Ãssea o aspirado para o mielograma e 4 a 5 ml, em 2 ml de heparina, para a avaliaÃÃo citogenÃtica por bandaâG. A anÃlise dos dados foi realizada utilizando os programas estatÃsticos Biostat 4.0 e GraphPad Prism (versÃo 5.0), o teste Coeficiente de Phi e o teste Coeficiente de Contingencia C. Os testes de Fisher e Qui-quadrado com Ãndice de significÃncia α = 5%. Kaplan-Meier para funÃÃo de sobrevivÃncia e o teste log rank. Os resultados foram gerados usando o software livre R, versÃo 2.7. Resultados: Os pacientes (74,42%) tinham idade acima de 60 anos; 58,14% homens e 41,86% mulheres; a maioria (32,56%) trabalhava na agricultura; pardos (74,42%), procedentes da capital (53,49%); histÃria familiar de LLC desconhecida (46,51%); sintomÃticos ao diagnÃstico (53,49%); com comorbidades (hipertenÃÃo arterial e Diabetes Melitus) (51,16%); estÃgio 0 (34,89%), I e II (51,16%), III e IV (13,95%) de Rai; A (44,19%), B (44,19%) e C (11,62%) de Binet ; tempo de duplicaÃÃo linfocitÃra (TDL) ausente (81,40%); biÃpsia da medula Ãssea com padrÃo nÃo difuso (57,14%); a desidrogenase lÃctica (LDH) normal (83,72%), avaliados ao diagnÃstico. Os exames obtidos durante a evoluÃÃo dos pacientes revelaram um perfil imunofenotÃpico clÃssico de LLC- B, com expressÃo de CD5+, CD19+, CD23+ e imunoglobulina de superfÃcie de baixa expressÃo; a maioria com Zap-70 negativa (77,50%); expressÃo de CD38 negativa (73,81%); Ã2-M aumentada (55,81%); cariÃtipo normal (44,4%) e alteraÃÃes genÃticas em 11, 11% pela citogenÃtica clÃssica. As curvas de sobrevidas dos pacientes com Zap-70 e CD38 negativos apresentaram maior tempo de sobrevida livre de tratamento. ConclusÃo:Os pacientes avaliados eram idosos, com tendÃndia ao diagnostico tardio decorrente do contexto socioeconÃmico; apresentaram LLC indolente, pelos critÃrios de estadiamentos clÃssicos (Rai, Binet, TDL, padrÃo da histologia da medula Ãssea, LDH) e biolÃgicos (as expressÃes da Zap-70 e CD38), exceÃÃo à Ã2-M, porÃm, sem significÃncia. Aqueles com Zap-70 e CD38 negativos apresentaram maior sobrevida livre de tratamento. Pacientes do sexo masculino apresentaram evoluÃÃo e prognÃstico semelhantes ao feminino. O tratamento prevalente foi clorambucil associado à prednisona e nÃo levou os pacientes à remissÃo clÃnica ou hematolÃgica. Os marcadores de prognÃsticos tenderam à correlaÃÃo na identificaÃÃo dos pacientes dentro dos subgrupos de riscos. / Introduction: Chronic lymphocytic leukemia (CLL) is a neoplasm characterized by clonal proliferation of lymphocytes of mature appearance. Clinically and prognostic heterogeneous. Rai and Binet established clinical prognostic systems that classify LLC in low, intermediate and high risk. Soon, the biological markers of prognosis that increased the predictive power of the LLC. Objective: To characterize the clinical and biological markers of pognÃstico of patients with CLL the outpatient department of a university hospital (HUWC) / Center for Hematology and Hemotherapy Cearà / HEMOCE). Methodology: This is a retrospective, cross-sectional and observational 43 patients LLC, recruited so randomisation, from August 2007 to June 2009. We collected patient data from medical records, interview and three samples with 5.0 ml of peripheral venous blood in ethylenediaminetetraacetic acid (EDTA) for blood, for automated methodology CellDyn  equipment, model 3500, measurement of Ã2-microglobulin (Ã2 - M) serum by automated quantitative test on the device MINI-VIDAS (BioMÃrieux Â) and immunophenotyping on flow cytometry Beckman Coulter  EPICS XL-MCL (Coulter). Then collect the puncture of bone marrow aspirate and bone marrow examination for 4 to 5 ml in 2 ml of heparin for cytogenetic evaluation by Banda - G. Data analysis was performed using the statistical programs Biostat 4.0 and GraphPad Prism (version 5.00), the Phi coefficient test and the test coefficient Contingency C. The Fisher and chi-square test with significance level α = 5%. Kaplan-Meier survival function and log rank test. The results were generated using the free software R, version 2.7. Results: The patients (74.42%) were aged over 60 years, 58.14% 41.86% men and women, the majority (32.56%) worked in agriculture; brown (74.42%), coming the capital (53.49%), family history of unknown LLC (46.51%), symptomatic at diagnosis (53.49%), with comorbidity (arterial hypertension and Diabetes Mellitus) (51.16%), stage 0 ( 34.89%), I and II (51.16%), III and IV (13.95%) Rai, A (44.19%), B (44.19%) and C (11.62%) of Binet, lymphocyte doubling time (SRT) absent (81.40%), bone marrow biopsy with non-diffuse pattern (57.14%), lactate dehydrogenase (LDH) normal (83.72%), valued at diagnosis. The tests obtained during the course of the patients showed an immunophenotypic profile of classic B-CLL with expression of CD5 +, CD19 +, CD23 + surface immunoglobulin and low-expression, most with Zap-70 negative (77.50%); expression CD38 negative (73.81%), beta-2 microglobulin increased (55.81%), normal karyotype (44.4%) and genetic alterations in 11, 11% by classical cytogenetics. Survival curves of patients with Zap-70 negative and CD38 showed longer survival free of treatment. Conclusion: The patients studied were elderly, to encourage improve with late diagnosis due to the socioeconomic context, LLC indolent presented by classical staging criteria (Rai, Binet, TDL, standard bone marrow histology, LDH) and biological (the expression of Zap -70 and CD38), except for beta-2 microglobulin, but without statistical significance. Those with Zap-70 and CD38 negative had higher survival free of treatment. Male patients showed progress and prognosis similar to female. The prevalent treatment was associated with chlorambucil prednisone and did not lead patients to clinical remission or hematologic. The prognostic markers of the correlation tended to identify patients within the subgroups of risk.

Les récepteurs du Fc des Immunoglobulines G (FcγR) sont impliqués dans de nombreuses réactions immunitaires. Deux groupes de faible affinité existent : les FcγRIIa/b/c et les FcγRIIIa/b, FcγRIIb étant le seul inhibiteur. Plusieurs polymorphismes, modifiant l’affinité au ligand et la réponse du récepteur, sont favorisés par une pression de sélection infectieuse et associés aux Maladies Auto-Immunes (MAI). Nous avons étudié l’association des polymorphismes FcγRIIa-R131H, FcγRIIb-I232T, FcγRIIIa-F158V, FcγRIIIb-Na1/Na2 aux Lupus érythémateux systémique (LES), la neuromyélite optique (NMO) et la sclérose en plaque (SEP) en Martinique. Nos résultats montrent une forte fréquence des allèles T232, V158 et des génotypes 232TT et 158VV dans la population générale, une augmentation de la fréquence de l’homozygote Na1, des allèles Na1 et 158F dans le LES, une augmentation du génotype 131RR ainsi que des allèles 131R et 158V dans le LES avec atteinte rénale, une augmentation du génotype 131RR et une diminution du NA2/NA2 dans la SEP ainsi qu’une augmentation de l’allèle 232T dans les NMO. L’étude de l’influence du FcγRIIb-I232T sur l’activation du récepteur à l’antigène des lymphocytes B (BCR) chez des lupiques et des témoins sains porteurs des formes IT, TT ou II montre que la régulation du BCR est effective même en présence de la forme TT. Ces résultats démontrent pour la première fois que la population martiniquaise possède un terrain génétique particulier qui faciliterait l’apparition de MAI avec pronostic plus sévère. / Receptors of Fc of Immunoglobulin G (FcγR) are involved in many immune responses. Two low affinity groups exist: FcγRIIa/b/c, and FcγRIIIa/b, FcγRIIb is the only inhibitor. Several polymorphisms, altering the affinity ligand and receptor response, are selected by an infectious pressure and associated with autoimmune diseases (AID). We studied the association of polymorphisms FcγRIIa-R131H, FcγRIIb-I232T, FcγRIIIa-F158V, FcγRIIIb-Na1/Na2 to systemic lupus erythematosis (SLE), neuromyelitis optica (NMO) and multiple scelrosis (MS) in Martinique. Our results show a high frequency of alleles T232, V158 and 232TT and 158VV genotypes in Martinican, an increase in the frequency of the homozygous Na1, Na1 and 158F alleles in SLE, an increase of 131RR genotype, the 131R and 158V alleles in SLE with kidney disease, an increase of 131RR genotype and a decrease of NA2 / NA2 in MS but an increase in the 232T allele in NMO. Study of the influence of FcγRIIb-I232T on the activation of the B cells receptor (BCR) in lupus and healthy controls controls exibiting IT, TT or II forms, shows that the regulation of BCR is effective even in the presence TT form. These results show for the first time Martinican population has a particular genetic background which would facilitate the appearance of MAI particularly serious.

Lors de la reconnaissance de leur antigène spécifique, les lymphocytes B vont s’activer et interagir avec les autres cellules des organes lymphoïdes secondaires (cellules folliculaires dendritiques, lymphocytes T, …) pour former un centre germinatif où le locus IgH va être remanié afin d’accroitre l’affinité des immunoglobulines pour l’antigène (grâce à l’hypermutation somatique des régions variables (SHM) et de décliner l’activité effectrice des anticorps selon plusieurs types de fonction grâce à la commutation de classe des régions constantes ou « switch u CSR», afin d’éliminer selon diverses stratégies l’antigène . Ces deux mécanismes sont initiés par l’Activation Induced Deaminase (AID) qui cible l’ADN au niveau des cytosines pour les changer en uracile, aboutissant à des cassures simple brin ou double brin lorsque que les mésappariements sont proches les uns des autres.Il a été montré qu’AID est capable de cibler la région régulatrice en 3’ du locus IgH au niveau de régions LS, action qui aboutit à la délétion complète des gènes C du locus, à la perte de l’expression du BCR et à la mort cellulaire lors de la recombinaison suicide du locus (LSR). Dans notre étude, nous avons réalisé un modèle knock-in du gène Cμ humain en aval de la dernière région LS dans le but de sauver les cellules B réalisant la LSR sur les dernières régions LS par l’expression d’un BCR humanisé (modèle LSR-μKI). Notre modèle indique que l’insertion du gène Cμ humain en aval de l’élément hs4 de la 3’RRpermet en effet de remplacer certaines recombinaisons LSR par un switch vers l’expression d’IgM humanisée », et module en outre qualitativement certains aspects de la réponse immunitaire humorale. Notre modèle « rapporteur » de la LSR suggère aussi que l’évènement de LSR est un phénomène régulé qui augmente avec l’activation B. L’étude ex vivo de cellules B issues du modèle suggère que la LSR est possible lors d’une réponse T indépendante comme T dépendante. Elle se montre aussi inductible par les ligands TLR4 mais non TLR9. L’étude du répertoire des IgM humaines indique une utilisation biaisée des familles de VH, avec notamment sur utilisation de la famille VH5murine, suggérant donc que l’incidence de la LSR varie avec la structure des régions variables du BCR et pourrait donc être dépendante de l’affinité contre des antigènes/ligands qui restent à caractériser. / After antigen recognition, B cells are activated and interact with other cells within secondarylymphoid organs (dendritic cells, T lymphocytes …) to form a germinal center. In the GC, the IgH locusis reorganized in order to increase the affinity of immunoglobulins for antigen through somatichypermutation (SHM) of V(D)J regions and to configure them into several forms harboring diversifiedmodes of action after “class switc recombination” (CSR). Both mechanisms are initiated by ActivationInduced Deaminase (AID) which targets DNA cytosines to convert them into uracil, then causing singleor double strand breaks in DNA when the mismatchs are located close to each other. It has been shownthat AID can target the IgH locus 3’ regulatory region on specific regions called LS, then leading to thetotal deletion of IgH locus C genes, loss of BCR expression and cell death by locus suicide recombination(LSR). In our study, we created a human Cμ knock-in model distal to the hs4 element of the 3’RR, in anattempt to rescue cells after the LSR event. Our model showed that this insertion indeed succeededinto replacing LSR by “class switching to humanized IgM” and also qualitatively modulated someaspects of the humoral response. This new LSR reporter model additionally supports the hypothesisthat LSR is regulated and increases with B cell activation. Studies of ex vivo B cells from the modelsuggest that LSR can occur in T dependent and independent manners, but is induced by triggering TLR4but not TLR9. Studies of the human IgM repertoire showed a biased use of VH families, and notably themouse VH5 family was used more frequently than in the control group. The BCR repertoire bias stronglysuggests that LSR is at least in part a matter of affinity of the BCR variable regions for antigens andligands that remain to be characterized.

To supplement and modify the diagnosis and clinical research of B-cell Chronic Lymphocytic Leukemia (B-CLL), a new method based on cell imaging and image processing was developed and applied to the B-CLL patient samples. The fluorophore-labelled leukemia cells were clearly visualized, reflecting the positive/negative expression of the corresponding surface markers and their distribution. Computer algorithms were devised and used to analyze a large number of images. The fluorescence intensity of the labelled antibodies on a given cell directly reflects the expression of the corresponding surface markers. The morphology and size of leukemia cells were not identical even in the same patient’s sample and the size variation does not correlate with the number of surface markers. The amount of each surface marker was approximately fixed for each patient, but there were some relationships, for instance, the number of CD19 and CD38 markers were correlated to each other. The heterogeneous expression of surface markers confirmed an assumption that surface markers have their preferred membrane positions. One of the most important results is that the cell imaging and our image processing method has provided an alternative and reliable way to diagnose B-CLL and new insights in the prognosis of subtype of B-CLL.

Les polynucléaires neutrophiles ont longtemps été considérés comme des cellules n’intervenant que dans la réponse immune innée. Cependant, au cours de ces dernières années, de nombreuses publications suggèrent que ces cellules, retrouvées au sein du microenvironnement de nombreux cancers, pourraient également jouer un rôle dans la tumorigénèse et la progression tumorale. Ces études mettent en évidence leur fréquence comme marqueur pronostique dans différents cancers solides, mais peu de travaux se sont intéressés à la caractérisation fonctionnelle de ces cellules dans la progression tumorale. Dans de nombreux cancers dont les lymphomes B issus du centre germinatif, les cellules tumorales, qui sont incapables de proliférer et de survivre seules, sont dépendantes de leur microenvironnement de soutien. Dans cette étude, nous avons évalué la fonctionnalité des polynucléaires neutrophiles dans la croissance des lymphomes B. Ainsi, nous avons démontré pour la première fois que les polynucléaires neutrophiles soutiennent directement la croissance et la survie des cellules tumorales de lymphomes B. De plus, un dialogue bidirectionnel existe entre les polynucléaires neutrophiles et les cellules stromales. D’une part, les cellules stromales soutiennent la survie des polynucléaires neutrophiles, qui en retour induisent les caractéristiques d’un stroma lymphoïde. L’induction de ce phénotype permet aux cellules stromales d’acquérir de meilleures capacités de soutien envers les cellules tumorales. Cette étude confirme donc que les polynucléaires neutrophiles sont une composante importante du microenvironnement tumoral, et pourraient devenir une nouvelle cible thérapeutique pour le traitement des lymphomes B issus du centre germinatif. / For long time, neutrophils have only been considered as cells involved in the innate immune response. More recently, in descriptive publications, neutrophils were found in the microenvironment of many solid cancers, hypothesizing that they could also play a role in tumorigenesis and cancer progression. These studies highlighted the prognostic value of their frequency, but few of them focused on the functional characterization of these cells in tumor growth. In many cancers, including germinal centre-derived B-cell lymphomas, tumor cells are dependent on their microenvironment to proliferate and survive. In this study, we focused on the role of neutrophils in the progression of B-cell lymphomas, and for the first time we demonstrated that neutrophils directly support the growth and survival of tumor Bcells. In addition, we highlighted the existence of bidirectional cooperation between neutrophils and stromal cells. In one hand stromal cells support the survival of neutrophils. On the other hand, neutrophils induce a lymphoid stroma phenotype which is well known to enhance their supportive effect on tumor cells. This study demonstrates that neutrophils are a significant component of the tumor microenvironment and may be considered as a potential therapeutic target for the treatment of B-cell lymphomas.

No description available.

Thesis (M.A.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / High dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) who are chemosensitive to salvage therapy. There is now evidence that the achievement of complete remission by PET scan (PET-CR) after salvage therapy is a favorable determinant of ASCT outcome, implying that PET response should be part of the prognostic assessment for patients considering ASCT. However, it is unclear whether other prognostic factors are still relevant in patients getting post-salvage PET scanning. Moreover, while ASCT is often also used for patients with R/R transformed indolent lymphoma (TIL), there are no data on whether prognostic factors that are important for DLBCL patients, especially PET response to salvage, are similarly prognostic in this population. We conducted a retrospective study of 143 patients with R/R DLBCL and TIL who were transplanted in the last decade and had a post-salvage PET scan prior to ASCT. We examined prognostic factors in both groups, and constructed a prognostic score for DLBCL patients. For patients with DLBCL, post-salvage PET response was an important prognostic factor. Advanced age and symptomatic relapse were also significantly associated with inferior outcome. A simple score could stratify patients into 3 risk groups with 4-year post-ASCT overall survival of 84%, 59%, and 10%, and 4-year progression-free survival of 67%, 41% and 0% (p<0.0001 for both). However, none of those factors (including PET response to salvage) could be demonstrated for TIL, likely because of the limited sample size. Our novel prognostic score for DLBCL patients undergoing ASCT may be useful for prognostication, for stratification in clinical trials, and to motivate the design of new strategies for patients in the highrisk group, who may not derive benefit from standard ASCT. Those factors, however, do not apply to patients with TIL, which has important implications for their treatment and inclusion in ASCT clinical trials with larger sample sizes. / 2031-01-01

<p>Difuzni krupnoćelijski B limfom je najče&scaron;ći limfom na svetu i obuhvata do 30% non Hodgkin limfoma u zapadnim zemljama i veći procenat u zemljama u razvoju i nerazvijenim zemljama. Obično nastaje de novo ali može nastati sekundarno kao rezultat progresije manje agresivnih limfoma. U većini slučajeva počinje u limfnim čvorovima. Histolo&scaron;ka slika nije uniformna kod svih podtipova DLBCL, zbog morfolo&scaron;kog diverziteta tumorskih ćelija i zbog pratećih neneoplastičnih procesa. Na&scaron;e istraživanje obuhvata 92 bolesnika koji su dijagnostikovani i lečeni na Institutu za onkologiju Vojvodine od 2003. do 2011. godine, od kojih je 66 imalo kompletna imunohistohemijska ispitivanja. Svi su lečeni standardnim protokolom koji uključuje rituksimab. Ispitivali smo morfolo&scaron;ki i imunohistohemijski podtip, ekspresiju imunohistohemijskih markera, pol, starost, stadijum, nodalno/ekstranodalno ishodi&scaron;te i preživljavanje. CD20 je bio pozitivan u svim dostupnim uzorcima. MUM1 u 62,07%, CD10 u 20,23%, BCL6 u 51,72%, CD30 u 10,81%, CD5 u 8,05%, Ki-67 u 30-92%, BCL2 u 39,33%, BAFFR u 46,15%, TACI u 43,94%, BCMA u 10,61%, VEGF u 27,7%, COX2 u 63,64%, CD43 u 18,52%, EBV LMP u 37,88%. Među obolelim ženama je statistički značajno veći procenat MUM1 pozitivnih i BAFFR pozitivnih bolesnika nego među obolelim mu&scaron;karcima. Kod starijih ispitanika je statistički signifikantno ređa ekspresija CD30, COX2, TACI i BCMA. Kod ekstranodalnih limfoma ekspresija TACI je če&scaron;ća nego kod nodalnih limfoma. Ispitanici sa pozitivnom ekspresijom COX2 i ispitanici sa pozitivnom ekspresijom TACI imaju značajno izraženiju ekspresiju Ki-67. Bolesnici sa negativnom ekspresijom BCL2 imaju statistički značajnu korelaciju sa negativnom ekspresijom CD5 i negativnom ekspresijom CD43. Bolesnici sa pozitivnom ekspresijom CD30 imaju statistički značajnu pozitivnu korelaciju sa ekspresijom BCMA. Ispitanici sa pozitivnom ekspresijom COX2 imaju statistički značajnu pozitivnu korelaciju sa ekpresijom TACI. Markeri aktivacije i diferencijacije limfocita nemaju statistički značajnu pozitivnu korelaciju sa boljom prognozom. Markeri signalnih puteva angiogeneze i inflamacije nemaju statistički značajnu pozitivnu korelaciju sa lo&scaron;ijom prognozom. Izgleda da treba biti racionalan i upotrebiti samo osnovna antitela za određivanje imunohistohemijskog podtipa i antitela potrebna za diferencijalnu dijagnozu. Čini se da je prognostički značaj imunohistohemijskih antitela (osim CD20) danas kada se u terapiji koristi Rituximab minimalan.</p> / <p>Diffuse large B-cell lymphoma is the most common lymphoma in the world and represents up to 30% of all NHL in western countries and more in developing and undeveloped countries. It is usually a primary disease but also it can develop secondary as a result of progression of low grade lymphomas. In most cases the disease begins in lymph nodes. Histological features are not uniform in all subtypes of DLBCL due to morphological diversity and following non-neoplastic processes. Our research includes 92 patients whom are diagnosed and treated at the Institute for Oncology of Vojvodina since 2003. to 2011. and 66 among them have complete immunohistochemical findings. All of them are treated with standard protocols including Rituximab. We have examined morphological and immunohistochemical subtype, expression of immunohistochemical markers, sex, age, stadium, nodal / extranodal origin and survival. CD20 was positive in all available samples. MUM1 in 62,07%, CD10 in 20,23%, BCL6 in 51,72%, CD30 in 10,81%, CD5 in 8,05%, Ki-67 in 30-92%, BCL2 in 39,33%, BAFFR in 46,15%, TACI in 43,94%, BCMA in 10,61%, VEGF in 27,7%, COX2 in 63,64%, CD43 in 18,52%, EBV LMP in 37,88%. Female patients have significantly more often MUM1 and BAFFR expression compared to male patients. Older patients have significantly less often CD30, COX2, TACI and BCMA expression. Extranodal lymphomas have more frequent TACI expression then nodal ones. Patients with COX2 expression and patients with TACI expression have significantly higher Ki-67 expression. Patients without BCL2 expression have a significant correlation with CD5 negative expression and CD43 negative expression. Patients with CD30 expression have significant correlation with BCMA expression. Patients with COX2 expression have significant correlation with TACI expression. Markers of activation and differentiation of lymphocytes do not have significant correlation with better prognosis. Markers of signaling pathways for angiogenesis and inflammation do not have a significant correlation with worst prognosis. It seems that we should be rational and use only basic antibodies for determination if immunohistochemical subtype and antibodies necessary for differential diagnosis. It seems that prognostic significance of immunohistochemical antibodies (except CD20) is minimal today in Rituximab era.</p>

INTRODUCTION: Chimeric antigen receptor (CAR) T-cell therapy is a new treatment for hematologic malignancies including aggressive B-cell non-Hodgkin’s lymphoma (NHL). Although it has provided an effective treatment option for patients who have few options, CAR T-cell therapy does have many associated toxicities. Prolonged cytopenias are one of the lesser understood toxicities that can affect upwards of 40% of patients. METHODS: In this retrospective study, we reviewed 106 patients who received commercial CAR T-cell therapy between November 2017 and September 2019. Prolonged cytopenias were defined as having absolute neutrophil count (ANC) <1000/mm3, platelets (PLT) <50,000/mm3, and/or hemoglobin (Hgb) <10 g/dL at least once after 30 days post-CAR T-cell infusion. Furthermore, if only one incidence of cytopenia was recorded 30 days post infusion, we required that the patient had to have received either a transfusion or granulocyte-colony stimulating factor (GCSF) after the date of the recorded cytopenic value to be considered a part of the cytopenic cohort. RESULTS: 22 patients met the criteria of having prolonged cytopenias. 64% of the cytopenic cohort had >1 type of prolonged cytopenias. Anemia was the most prevalent affecting 72% of cytopenic patients. The length of time from diagnosis of aggressive B-cell NHL to date of CAR T-cell infusion was found to be positively correlated with an increased risk of developing prolonged cytopenias following CAR T-cell therapy. Additional risk factors associated with an increased risk of delayed cytopenias by univariate analysis included neutropenia on the day of infusion (day 0), a high C-reactive protein (CRP) before lymphodepletion and on day 0, day 0 PLT count, and Hgb before lymphodepletion and on day 0. On multivariate analysis, only high CRP before lymphodepletion was associated with an increased risk of prolonged cytopenias while high ferritin and PLT values on day 0 were associated with not developing prolonged cytopenias. There was no statistical difference between the cytopenic and non-cytopenic cohorts in rates of progression free survival (PFS) and overall survival (OS). Also, no difference was seen in rates or severity of other toxicities between cohorts. 41% of the cytopenic cohort experienced infectious complications post-infusion with one patient dying from their infectious complications. However, there was no association with incidence of infection and prolonged cytopenias when compared to the incidence of infection in the non-cytopenic cohort. CONCLUSIONS: A longer time from diagnosis of aggressive B-cell NHL to time of CAR T-cell infusion was associated with prolonged cytopenias while the number of lines of prior chemotherapy and rate of prior high dose chemotherapy with an autologous stem cell transplant (HD-ASCT) were not associated. It would be valuable to confirm this association and why it is associated since the other two factors were not. We lacked bone marrow biopsies before CAR T-cell infusion and did not have bone marrow biopsies for many patients after CAR T-cell infusion. It would be beneficial to collect data regarding bone marrow biopsies from these time points to highlight any changes that could be related to CAR T-cell therapy. Cytogenetic information of individual patient’s diseases would be worth analyzing to help determine if there are biological factors associated with prolonged cytopenias in response to CAR T-cell therapy. Additional studies should investigate the laboratory values we found to have associations with either cohort to help identify possible predictive values providers could use to identify patients at higher risk of having prolonged cytopenias. There is also a need to see if specific prior chemotherapy regimens increase a patient’s risk of having prolonged cytopenias. Overall, since prolonged cytopenias after CAR T-cell infusions have not been heavily investigated, further investigation is needed to better understand the predictive factors and identify possible mechanisms of prolonged cytopenias seen in CAR T-cell patients.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22727号 / 医博第4645号 / 新制||医||1045(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 濵﨑 洋子, 教授 羽賀 博典, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM