Follicular lymphoma in the palate with clinical appearance similar to salivary gland tumors

Intraoral presentation of follicular lymphoma is rare, and only three cases in the palate have been reported to date. The present case report describes an uncommon case of follicular lymphoma affecting the palate. The clinical aspect was similar to salivary gland neoplasm, and an incisional biopsy was important to establish the correct diagnosis and consequently to plan the treatment. Also discussed is the differential diagnosis among follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, and follicular lymphoid hyperplasia with regard to the histopathologic and immunohistochemical features. (Quintessence Int 2010; 41: 661-663)

Biological predictors of survival in limphoma and mechanisms underlying follicular lymphoma transformaion into diffuse large B cell lymphoma (vol I e II)

RESUMO: Os biomarcadores tumorais permitem identificar os doentes com maior risco de recorrência da doença, predizer a resposta tumoral à terapêutica e, finalmente, definir candidatos a novos alvos terapêuticos. Novos biomarcadores são especialmente necessários na abordagem clínica dos linfomas. Actualmente, esses tumores são diagnosticados através de uma combinação de características morfológicas, fenotípicas e moleculares, mas o prognóstico e o planeamento terapêutico estão quase exclusivamente dependentes de características clínicas. Estes factores clínicos são, na maioria dos linfomas, insuficientes numa proporção significativa dos doentes, em particular, aqueles com pior prognóstico. O linfoma folicular (LF) é, globalmente, o segundo subtipo mais comum de linfoma. É tipicamente uma doença indolente com uma sobrevida média entre os 8 e 12 anos, mas é geralmente fatal quando se transforma num linfoma agressivo de alto grau, habitualmente o linfoma difuso de grandes células B (LDGCB). Morfologicamente e funcionalmente, as células do LF recapitulam as células normais do centro germinativo na sua dependência de sobrevivência do microambiente não-tumoral, especialmente das células do sistema imunológico. Biomarcadores preditivos de transformação não existem pelo que um melhor conhecimento da biologia intrínseca de progressão do LF poderá revelar novos candidatos. Nesta tese descrevo duas abordagens distintas para a descoberta de novos biomarcadores. A primeira, o estudo da expressão global de genes ('genomics') obtidos por técnicas de alto rendimento que analisam todo o genoma humano sequenciado, permitindo identificar novas anomalias genéticas que possam representar mecanismos biológicos importantes de transformação. São descritos novos genes e alterações genómicas associados à transformação do LF, sendo especialmente relevantes as relacionadas com os eventos iniciais de transformação em LDGCB. A segunda, baseou-se em várias hipóteses centradas no microambiente do LF, rico em vários tipos de células nãomalignas. Os estudos imunoarquitectural de macrófagos, células T regulatórias e densidade de microvasos efectuado em biopsias de diagnóstico de doentes com LF tratados uniformemente correlacionaram-se significativamente, e independentemente dos critérios clínicos, com a evolução clínica e, mais importante, com o risco de transformação em LDGCB. Nesta tese, foram preferencialmente utilizadas (e optimizadas) técnicas que permitam o uso de amostras fixadas em parafina e formalina (FFPET). Estas são facilmente acessíveis a partir das biopsias de diagnóstico de rotina presentes nos arquivos de todos os departamentos de patologia, facilitando uma transição rápida dos novos marcadores para a prática clínica. Embora o FL fosse o tema principal da tese, os novos achados permitiram estender facilmente hipóteses semelhantes a outros subtipos de linfoma. Assim, são propostos e validados vários biomarcadores promissores e relacionados com o microambiente não tumoral, sobretudo dependentes das células do sistema imunológico, como contribuintes importantes para a biologia dos linfomas. Estes sugerem novas opções para a abordagem clínica destas doenças e, eventualmente, novos alvos terapêuticos.------------- ABSTRACT: Cancer biomarkers provide an opportunity to identify those patients most at risk for disease recurrence, predict which tumours will respond to different therapeutic approaches and ultimately define candidate biomarkers that may serve as targets for personalized therapy. New biomarkers are especially needed in the management of lymphoid cancers. At present, these tumours are diagnosed using a combination of morphologic, phenotypic and molecular features but prognosis and overall survival are mostly dependent on clinical characteristics. In most lymphoma types, these imprecisely assess a significant proportion of patients, in particular, those with very poor outcomes. Follicular lymphoma (FL) is the second most common lymphoma subtype worldwide. It is typically an indolent disease with current median survivals in the range of 8-12 years, but is usually fatal when it transforms into an aggressive high-grade lymphoma, characteristically Diffuse Large B Cell Lymphoma (DLBCL). Morphologically and functionally it recapitulates the normal cells of the germinal center with its survival dependency on non-malignant immune and immunerelated cells. Informative markers of transformation related to the intrinsic biology of FL progression are needed. Within this thesis two separate approaches to biomarker discovery were employed. The first was to study the global expression of genes (‘genomics’) obtained using high-throughput, wholegenome-wide approaches that offered the possibility for discovery of new genetic abnormalities that might represent the important biological mechanisms of transformation. Gene signatures associated with early events of transformation were found. Another approach relied on hypothesis-driven concepts focusing upon the microenvironment, rich in several non-malignant cell types. The immunoarchitectural studies of macrophages, regulatory T cells and microvessel density on diagnostic biopsies of uniformly treated FL patients significantly predicted clinical outcome and, importantly, also informed on the risk of transformation. Techniques that enabled the use of routine formalin fixed paraffin embedded diagnostic specimens from the pathology department archives were preferentially used in this thesis with the goal of fulfilling a rapid bench-to-beside” translation for these new findings. Although FL was the main subject of the thesis the new findings and hypotheses allowed easy transition into other lymphoma types. Several promising biomarkers were proposed and validated including the implication of several non-neoplastic immune cells as important contributors to lymphoma biology, opening new options for better treatment planning and eventually new therapeutic targets and candidate therapeutics.

Radioimmunotherapy consolidation and rituximab maintenance in the initial treatment of follicular lymphoma.

ABSTRACT: Several reports have documented similar efficacies and tolerable toxicities of radioimmunotherapy (RIT) consolidation and rituximab maintenance after initial R-chemotherapy of follicular lymphoma. The relative merits of these two interventions are currently under discussion. We now raise the question whether both RIT consolidation and rituximab maintenance should be used together aiming to augment the results achievable with R-chemotherapy.

Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98.

PURPOSE: We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma. PATIENTS AND METHODS: Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure). RESULTS: At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, at 8 years 45% were still without event. The only favorable prognostic factor for EFS in a multivariate Cox regression was the prolonged rituximab schedule (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P = .009), whereas being chemotherapy naive, presenting with stage lower than IV, and showing a VV phenotype at position 158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-term toxicity potentially due to rituximab was observed. CONCLUSION: An important proportion of patients experienced long-term remission after prolonged exposure to rituximab, particularly if they had no prior treatment and responded to rituximab induction.

Long-term follow-up of follicular lymphoma (FL) patients receiving single agent rituximab at two different schedules in trial SAKK 35/98

Background: In FL, Rituximab as a single agent delivered in the standard schedule (4 times weekly) may induce a response rate of 50−70% with an event-free survival (EFS) of 1−3 years according to patients' characteristics. Prolonged Rituximab exposure seems to improve EFS at least in responding patients and to increase the rate of longterm responders. Here we report long-term results of a clinical trial comparing single agent Rituximab delivered in the standard schedule versus prolonged exposure, with focus on the proportion of long-term responders and their characteristics. Material and Methods: Between 1998 and 2002, chemotherapy na¨ıve (n = 64) or pre-treated (n = 138) FL patients received Rituximab in the standard schedule. Those responding or with stable disease were randomized to no further treatment (observation, n = 78) or 4 additional doses of Rituximab given at 2-month intervals (prolonged exposure, n = 73). EFS was calculated from the first dose of standard schedule until progression, relapse, second tumor or death. Results: At a median follow up of 9.4 years and with all living patients having been followed for at least 5 years, the median EFS is 13 months for the observation and 24 months for the prolonged exposure arm (p = 0.0007). In the observation arm 13% had no event at 5-years and only 4% at 8 years, while in the prolonged exposure arm it was 27% at 5 years and remained 21% at 8 years. The only significant prognostic factor for EFS in a multivariate Cox regression was the prolonged Rituximab schedule (hazard ratio 0.58, CI 0.39−0.86, p = 0.007), whereas being chemotherapy na¨ıve, presenting with stage

Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma.

PURPOSE: We conducted an international, randomized, phase III trial to evaluate the efficacy and safety of consolidation with yttrium-90 ((90)Y)-ibritumomab tiuxetan in patients with advanced-stage follicular lymphoma in first remission. PATIENTS AND METHODS: Patients with CD20(+) stage III or IV follicular lymphoma, who achieved a complete response (CR)/unconfirmed CR (CRu) or partial response (PR) after first-line induction treatment, were randomly assigned to receive (90)Y-ibritumomab tiuxetan (rituximab 250 mg/m(2) on day -7 and day 0 followed on day 0 by (90)Y-ibritumomab tiuxetan 14.8 MBq/kg; maximum of 1,184 MBq) or no further treatment (control). The primary end point was progression-free survival (PFS), which was calculated from the time of random assignment. RESULTS: A total of 414 patients (consolidation, n = 208; control, n = 206) were enrolled at 77 centers. (90)Y-ibritumomab tiuxetan consolidation significantly prolonged median PFS (after a median observation time of 3.5 years) in all patients (36.5 v 13.3 months in control arm; hazard ratio [HR] = 0.465; P &lt; .0001) and regardless of whether patients achieved PR (29.3 v 6.2 months in control arm; HR = 0.304; P &lt; .0001) or CR/CRu (53.9 v 29.5 months in control arm; HR = 0.613; P = .0154) after induction treatment. Median PFS with consolidation was prolonged in all Follicular Lymphoma International Prognostic Index risk subgroups. After (90)Y-ibritumomab tiuxetan consolidation, 77% of patients in PR after induction converted to CR/CRu, resulting in a final CR rate of 87%. The most common toxicity with (90)Y-ibritumomab tiuxetan was hematologic, and grade 3 or 4 infections occurred in 8% of patients. CONCLUSION: Consolidation of first remission with (90)Y-ibritumomab tiuxetan in advanced-stage follicular lymphoma is highly effective with no unexpected toxicities, prolonging PFS by 2 years and resulting in high PR-to-CR conversion rates regardless of type of first-line induction treatment.

Lymphoblastic transformation of follicular lymphoma: a clinicopathologic and molecular analysis of 7 patients.

Approximately 30% of patients with follicular lymphoma (FL) transform to a more aggressive malignancy, most commonly diffuse large B cell lymphoma. Rarely, FL transformation results in clinical findings, histology, and immunophenotype reminiscent of B-lymphoblastic leukemia/lymphoma. We report the largest series to date with detailed analysis of 7 such patients. Lymphoblastic transformation occurred on average 2 years after initial diagnosis of FL. Five patients had prior intensive chemotherapy. Two patients developed mature high-grade lymphoma, followed by the lymphoblastic transformation. FL had BCL2 gene rearrangement in 4 of 5 cases. High-grade transformation was accompanied by MYC gene rearrangement (5 of 5). Transformation was characterized by expression of TdT, loss of Bcl6, variable loss of immunoglobulin light chain, and persistence of Pax-5, Bcl2, and CD10. Whole-exome sequencing in 1 case revealed presence of several actionable mutations (CD79B, CCND3, CDK12). FL, aggressive mature B cell lymphoma, and lymphoblastic transformation were clonally related in 6 evaluable cases. After transformation, survival ranged from 1 to 14 months. Four patients died of disease, 2 were in remission after stem cell transplant, and 1 was alive with disease.

Radiolabeled and native antibodies and the prospect of cure of follicular lymphoma

Advanced-stage follicular lymphoma is incurable by conventional treatment. Rituximab has been introduced in various combinations with chemotherapy and has resulted in a significantly superior treatment outcome compared with chemotherapy alone. Multiple studies have also shown the efficacy of radioimmunotherapy (RIT) both as a single agent and in combination with chemotherapy. Rituximab and RIT have clearly distinct mechanisms of action, the first acting exclusively as a biological treatment, while the second acts by a combination of biologic mechanisms and radiation effects. Despite the therapeutic efficacy of both approaches, the potential exists to further improve both modalities. Repeat administrations of RIT using appropriate radioisotopes for treatment of residual disease or new targeting strategies might afford additional benefits. Unlabeled antibody treatment could potentially benefit from the combination of antibodies directed against different target antigens or combination therapy with cytokines capable of further mobilizing patients' cellular defenses. In this review, we hypothesize that the combination of an optimized biological treatment together with radiolabeled antibodies and chemotherapy early in the disease course of advanced-stage follicular lymphoma may represent the best approach to achieve prolonged disease-free survival and eventually cure.

Radio-immunothérapie du lymphome folliculaire: un pas vers la guérison [Radioimmunotherapy of follicular lymphoma: a step towards cure?]

Advanced stage follicular lymphoma is incurable by conventional treatment. Important progress has been observed with the development of new therapies based on monoclonal antibodies and on the use of radioimmunotherapy (RIT) in the treatment of non-Hodgkin lymphomas (NHL). Rituximab in combination with chemotherapy in the upfront setting significantly improved treatment outcome as compared with chemotherapy alone. Different studies also indicate that RIT has an important role in the management of NHL and could be beneficial in combination with chemotherapy. These two new treatment options have clearly distinctive mechanisms of action, rituximab being an exclusively biological treatment and RIT adding targeted systemic radiation therapy. Both RIT and the unlabeled antibody treatments might be further improved by different strategies including repetition of RIT or combination of different antibodies. We present here our experience with RIT using 131I-tositumomab (Bexxar) and discuss different topics regarding RIT, like the use of different antibodies, the best choice of the radioisotope or the place of radio-imaging. From the therapeutic point of view, we argue that the debate should not be as to which one among antibody immunotherapy or RIT should be best added to chemotherapy, but that all three treatments might be optimally combined with the aim to get the highest chance of cure for advanced stage follicular lymphoma.

Follicular lymphoma at relapse after rituximab containing regimens: comparison of time to event intervals prior to and after (90) Y-ibritumomab-tiuxetan.

Radioimmunotherapies with Zevalin® (RIT-Z) showed encouraging results in patients with relapsed/refractory follicular lymphoma (FL), leading frequently to failure-free intervals longer than those achieved by the last previous therapy. We compared time-to-event variables obtained before and after RIT-Z in patients with relapsed FL, previously exposed to rituximab. All patients with relapsed non-transformed, non-refractory, non-rituximab-naïve FL who have been treated with RIT-Z in two different centres in Europe were included. Staging and response were assessed by contrast-enhanced CT in all patients; PET/CT was performed according to local availability. Event-free survival (EFS) and time to next treatment (TTNT) following the last previous therapy and after RIT-Z were compared. Pre-therapy characteristics were tested in univariate analyses for prediction of outcomes. A description of the patterns of relapse was also provided. Among 70 patients treated, only 16 fulfilled the inclusion criteria. They were treated with a median of 3 prior lines of chemo-immunotherapies, including a median of 2 rituximab-containing regimens; 6 patients had undergone myeloablative chemotherapy with autologous stem cell rescue (ASCT). Overall response rates were 10 (62%) CR/CRu, 3 (19%) PR and 3 (19%) PD; response rates were similar in patients with prior ASCT. After RIT-Z only few patients obtained EFS and TTNT longer than after the last previous therapy. All four patients receiving rituximab maintenance were without progression 12 months after RIT-Z. Relapses occurred in both previously and newly involved sites; a significant association was found between the number of pathologic sites involved prior to RIT-Z and subsequent TTNT. Despite the excellent response rate, the duration of response was shorter than the previous one confirming the known trend of relapses to occur earlier after subsequent treatments. Rituximab maintenance after RIT-Z showed encouraging results in terms of prolonging EFS, warranting further studies. Copyright © 2010 John Wiley &amp; Sons, Ltd.

Diagnosis and treatment of follicular lymphoma.

Follicular lymphoma is a slow-growing disease exhibiting a heterogeneous clinical course, with a subset of patients experiencing a rapid disease course in the first two years and some developing disease transformation to a more aggressive phenotype. The advent of highly effective therapies has resulted in an increasing number of patients who achieve long-term progression-free survival alongside a good quality of life. Monoclonal antibodies, such as rituximab, either alone or in combination with chemotherapy regimens or radioimmunotherapy have been used with significant improvements in outcome. New treatment strategies such as new antibodies, biologic agents or vaccination therapy are also under investigation for the treatment of relapsed or refractory disease, further expanding the available options for patients and physicians alike. This article presents an overview of the current therapeutic strategies for the management of follicular lymphoma, focusing on the issues encountered in clinical practice.

Dosimetry of 90Y-ibritumomab tiuxetan as consolidation of first remission in advanced-stage follicular lymphoma: results from the international phase 3 first-line indolent trial.

The objective of this analysis was to assess the radiation exposure associated with (90)Y-ibritumomab tiuxetan when used as consolidation therapy in adults with low or minimal tumor burden after first-line therapy of advanced follicular lymphoma (FL). METHODS: The patients who were enrolled in the phase 3 first-line indolent trial were 18 y or older, with CD20(+) grade 1 or 2 stage III or IV FL, and a partial response, complete response, or unconfirmed complete response to first-line chemotherapy. The patients were allocated randomly to receive a single infusion of unlabeled rituximab 250 mg/m(2) on day -7 and consolidation on day 0 with a single dose of (90)Y-ibritumomab tiuxetan, 14.8 MBq/kg, immediately after unlabeled rituximab, 250 mg/m(2), or no further treatment. On day -7, a subset of patients received an injection of 185 MBq of (111)In-ibritumomab tiuxetan immediately after unlabeled rituximab, 250 mg/m(2), for central dosimetry analysis. Correlations were assessed between organ radiation absorbed dose and toxicity, body weight, body mass index, and progression-free survival. RESULTS: Central dosimetry evaluations were available from 57 of 70 patients. Median radiation absorbed doses were 100 cGy (range, 28-327 cGy) for the red marrow and 72 cGy (range, 46-106 cGy) for the whole body. Radiation absorbed doses did not differ significantly between patients who had a partial response or complete response to initial therapy. Progression-free survival correlated significantly with the whole-body (r = 0.4401; P = 0.0006) and bone marrow (r = 0.2976; P = 0.0246) radiation dose. Body weight was significantly negatively correlated with whole-body radiation dose (r = -0.4971; P < 0.0001). Neither the whole-body radiation dose nor the bone marrow radiation dose correlated with hematologic toxicity. CONCLUSION: In patients with low or minimal residual tumor burden after first-line chemotherapy of advanced FL, whole-body and bone marrow exposure after (90)Y-ibritumomab tiuxetan consolidation showed a significant positive correlation with progression-free survival, whereas dosimetric data could not predict hematologic toxicity.