Activity In Follicular Lymphoma Research Articles

Enhancing CAR T Cell Activity in Follicular Lymphoma: Targeting BTLA Through Engineered Soluble HVEM Delivery

Enhancing CAR T Cell Activity in Follicular Lymphoma: Targeting BTLA Through Engineered Soluble HVEM Delivery

A concise review of lenalidomide therapy for follicular lymphoma

ABSTRACTIntroduction: Lenalidomide, first introduced for the treatment of multiple myeloma in 2008, has been used in the treatment of various subtypes of non-Hodgkin lymphoma (NHL). Considering its mechanism of action, it has been associated with rituximab, showing strong activity in follicular lymphomas (FL). As the chemo-free treatments are a topic of great relevance we decided to prepare a concise review mainly directed to clinicians involved in the management of NHL patients.Areas covered: This article reviews the clinical trials published since 2008 utilizing lenalidomide alone or in combination for treating relapsed/refractory or treatment naïve patients with FL.Expert opinion: With current rituximab plus chemotherapy treatments, almost all patients will relapse from the disease over time. The introduction of lenalidomide in the management of FL showed good efficacy in particular in combination with rituximab (R2). The high rates of durable responses obtained with the R2 combination were similar to those previously observed with standard chemotherapy plus rituximab. If the results of the ongoing multicenter pivotal phase 3 trial (NCT01476787) are favorable for R2 combination, we may move towards a chemotherapy-free approach in the management of FL, which would finally turn a dream into reality.

Frontline strategy for follicular lymphoma: are we ready to abandon chemotherapy?

Chemotherapy combinations have been the backbone of therapy for follicular lymphoma, and are associated with high initial response rates. Unfortunately, toxicity and secondary malignancies remain concerns, and most advanced-stage patients still relapse within 5 years, regardless of the regimen. Advances in the understanding of lymphoma biology have resulted in a new generation of noncytotoxic therapeutics with significant activity in follicular lymphoma. Recent studies exploring biological and targeted combinations in the frontline have shown promise, with response rates similar to chemotherapy. However, these regimens are also associated with significant cost as well as a unique toxicity profile. Large randomized studies are underway to compare noncytotoxic regimens with chemotherapy in the frontline, and several new combinations are being tested in the phase 2 setting. Ongoing work to identify predictive biomarkers and investment in mechanistic studies will ultimately lead to the personalization of therapy in the frontline setting for follicular lymphoma.

Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (Alliance 051103)

Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (Alliance 051103)

The Optimal Management of Follicular Lymphoma: An Evolving Field

Follicular lymphoma consists of a heterogeneous group of diseases that can vary dramatically in clinical course. As with other indolent lymphomas, follicular lymphoma is felt to be highly treatable, but ultimately incurable. The appropriate management of this disease ranges from close observation to chemoimmunotherapy based on presenting symptoms and comorbidities. In this article, we focus on the optimal management of follicular lymphoma, including prognostication, indications for treatment, and current treatment options. While a number of front-line chemoimmunotherapy options exist, R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone) and BR (bendamustine, rituximab) tend to be favored due to efficacy and tolerability. Post-induction options include maintenance rituximab and radioimmunotherapy, but neither has demonstrated an overall survival benefit. In relapsed disease, patients can receive an alternative chemoimmunotherapy regimen or radioimmunotherapy, or participate in a clinical trial. There are a number of new biologic targeted therapies with promising activity in follicular lymphoma that have the potential to change our approach to this disease.

Constitutive Activity of Nuclear Transcription Factor κB is Observed in Follicular Lymphoma

Constitutive activity of nuclear transcription factor kappaB (NF-kappaB) is observed in many pathological types of lymphoma that are associated with a poor clinical course. This suggests that NF-kappaB and pathways involving NF-kappaB are possible targets for successfully treating lymphoma. We examined 28 lymph nodes from 28 patients in whom follicular lymphoma was diagnosed from 1996 to 2006 at our institution, which were formalin-fixed and paraffin-embedded. The specimens were stained with an antibody that could recognize activated NF-kappaB and p65 to determine whether they were positive or negative for NF-kappaB activation. The clinical courses of the 28 patients were then correlated with the results of the NF-kappaB staining. The 10 men and 18 women had a mean age of 57.3 years (range, 25-87 years). By follicular lymphoma grade, 10 patients had grade 1, 16 had grade 2, and 2 had grade 3a. Ten patients died due to lymphoma. NF-kappaB was positive in 6 of the 28 cases. Analysis of the positive and negative staining groups while taking into account the clinical course, sex, age, grade of follicular lymphoma, prognostic index, CD10, CD23, Bcl-2, karyotype t(14;18), and survival showed that no significant differences. Six of the 28 lymph nodes (21.4%) exhibited consistent NF-kappaB activity. Three of the eleven cases that transformed to aggressive lymphoma were positive for activated NF-kappaB. Further research to clarify the significance of constitutive NF-kappaB activity in follicular lymphoma is therefore warranted.

Optimal Application of Antibodies in the Treatment of Follicular Lymphoma: Current Standards and Future Strategies

Advanced-stage follicular lymphoma has previously been described as an incurable disease. However, the introduction of monoclonal antibodies such as rituximab has considerably changed the management of the disease in the last decade with a significant subset of patients remaining in remission for a decade or longer. Rituximab, a CD20-targeting antibody, is approved for treatment both upfront and in the relapse setting. The most dramatic impact of this antibody is observed in combinations with conventional chemotherapy regimens. Encouraging results have also been reported from radiolabeled anti-CD20 antibodies. High response rates and durable remissions have been seen with both (90)Y-ibritumomab tiuxetan and (131)I-tositumomab. However, refractoriness to immunochemotherapy still remains a problem, especially in relapsed disease. Several novel targeted agents show encouraging activity in follicular lymphoma. This review will focus on current treatment strategies in this disease.

Relative abundance of full-length and truncated FOXP1 isoforms is associated with differential NFκB activity in Follicular Lymphoma

FOXP1 is a transcriptional repressor that has been proposed to repress the expression of some NFκB-responsive genes. Furthermore, truncated forms of FOXP1 have been associated with a subtype of Diffuse Large B-cell Lymphoma characterised by constitutive NFκB activity, indicating that they may inhibit this repression. We have shown that FL tumors have increased relative abundance of truncated FOXP1 isoforms and this is associated with increased expression of NFκB-associated genes. Our results provide strong evidence that relative FOXP1 isoform abundance is associated with NFκB activity in FL, and could potentially be used as a marker for this gene signature.

Treatment of Follicular Non-Hodgkin's Lymphoma: The Old and the New

Despite remaining an incurable disease, overall survival improvements have been noted in patients with advanced-stage follicular lymphoma. The Follicular Lymphoma International Prognostic Index (FLIPI) is a robust prognostic index in this disease, and continues to provide prognostic information in the rituximab era. Rituximab has significantly changed the management of follicular lymphoma, and the most dramatic impact of rituximab is observed in combination with cytotoxic chemotherapy. However, resistance to rituximab remains a problem, and standard therapy in the rituximab-refractory setting includes radioimmunotherapy, autologous stem cell transplantation, and allogeneic stem cell transplantation. In addition, several novel agents show encouraging activity in follicular lymphoma, including bendamustine, lenalidomide, bortezomib, and other proteasome inhibitors, and BCL2 inhibitors.

Cladribine in indolent non-Hodgkin’s lymphoma

Before the advent of rationally designed targeted antineoplastic therapies, cladribine was identified as a lymphocyte-specific cytotoxic agent. Cladribine is a purine nucleoside analogue that is resistant to cellular catabolism. Through diverse mechanisms, cladribine is equally toxic to dividing and nondividing cells, making it highly active in indolent lymphoproliferative diseases. In clinical practice, cladribine is mostly used in the treatment of hairy cell leukemia and Waldenström’s macroglobulinemia. However, its remarkable activity in follicular lymphoma and other indolent non-Hodgkin’s lymphoma subtypes has not been more widely appreciated. Cladribine compares favorably to other standard treatments for these conditions. Future Phase III clinical studies should incorporate cladribine into multiagent chemotherapy programs to more fully evaluate its potential in indolent non-Hodgkin’s lymphoma.

The rituximab-PKCζ/Raf-1/mTOR connection

In this issue of Blood, Leseux and colleagues report rituximab-mediated inhibition of PKCζ activity in follicular lymphoma (FL) resulting in the inhibition of Raf-1 and mTOR signaling pathways and leading to inhibition of tumor cell proliferation.

Preliminary Results of a Phase I/II Study of Weekly or Twice Weekly Bortezomib in Combination with Rituximab, in Patients with Follicular Lymphoma, Mantle Cell Lymphoma and Waldenström's Macroglobulinaemia.

Introduction: Rituximab (R) is an integral component of therapy for B-cell lymphoid malignancies; bortezomib (Btz) has shown provocative single agent activity in Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) and Waldenström's Macroglobulinaemia (WM), providing the rationale for investigating the combination.Patients+Methods: Forty-five adult patients (pts.) (30 men, 15 women) with histologically confirmed recurrent CD20+ve FL, MCL or WM, median age 60 years (range 45-79), FL: 17, MCL: 18, WM: 10, stage III/IV 40 (93%), bone marrow (BM) infiltration 32 (73%), elevated LDH 22 (49%), performance status ≥1 22 (49%), were enrolled in a randomised trial comparing 2 schedules of Brz+R: Arm A (twice weekly) Btz: 1.3mg/m2 (on days 1, 4, 8, 11 of a 21-day cycle) and R: 375mg/m2 (on day 1) for 8 cycles, or Arm B (weekly) Btz: 1.6mg/m2 (on days 1, 8, 15, 22 of a 35-day cycle) and R: 375mg/m2 (on days 1, 8, 15, 22 of cycles 1 and 4) for 6 cycles (23 arm A, 22 arm B). The median number of previous treatments was 2 (range 1-7). Seventeen pts. had received a R-containing regimen, with response lasting >6 months, and 8 high-dose treatment. Response was evaluated using the IWR criteria (Cheson et al, JCO 17: 1244, 1999) and the updated response criteria from the 3rd International Workshop on WM (Treon et al, Blood 107: 3442, 2006)Results: Ability to deliver the therapy, toxicity and efficacy were equivalent in both arms. The median number of cycles given in arm A was 4 and 5 in arm B. Haematological toxicity (grade≥3: anaemia 0%, neutropenia 25%, thrombocytopenia 22%) was significantly influenced by the high percentage of pts. with BM infiltration and concomitant cytopenia on entry to the trial. The most common non-haematological adverse events were fatigue (76%), nausea (56%), diarrhoea (56%), lethargy (46%). Neurotoxicity occurred in 19 pts. (46%) (10 pts. grade 1, 7 pts. grade 2, 2 pts. grade 3). Btz dose was reduced in 7 pts.; 5 doses were omitted because of neuro or haematological toxicity. In 16 pts., treatment was delayed by 1-14 days and in 24 pts. treatment was stopped prematurely. The reasons for stopping treatment were: treatment-related toxicity 11 pts., progressive disease 9 pts., patient's preference 3 pts., myocardial infarction 1 pt. One pt. was excluded having been found ineligible post randomisation. Thirty-nine pts. (21 arm A, 18 arm B) are evaluable for response so far, one having only received 1 cycle of therapy, which had to be discontinued because of excessive toxicity. 15/32 were in remission (CR, CRu, PR) at the completion of therapy, 7/7 at “mid-therapy” assessment, and 5 have yet to be evaluated. Thus the overall response rate (RR) presently is 22/39 (56%) (CR, CRu, PR), FL 44%, MCL 46%, WM 90%.Conclusions:1.The combination was active in pts. with recurrent NHL especially WM (RR 90%), despite multiple previous treatments,2.The weekly schedule is preferable being more convenient, as efficacious and no more toxic.Further investigation is warranted, despite not insignificant therapy compromising toxicity.

Support for a Possible "Vaccinal" Effect of Rituximab; Lymphoma Idiotype Specific T-Cell Responses in Follicular Lymphoma Patients Treated with Rituximab.

Rituximab (Rtx) has shown significant therapeutic activity in follicular lymphoma (FL) patients, yet it's exact mechanism of action has not been fully defined. Although killing of FL cells through complement dependent cytolysis, antibody dependent cellular cytotoxicity or direct induction of apoptosis may contribute to its effectiveness, these mechanisms are unlikely to be the only ones as;a.the clinical and molecular responses to Rtx may continue for months after the last dose and;b.the median duration of the second response to Rtx is longer than that of the first, findings that cannot be explained solely by the above mechanisms.Rtx induced FL cell death likely results in the release of tumor antigens in a pro-inflammatory environment which we hypothesize may provoke a cell-mediated lymphoma specific immune response. Indeed, others have suggested that such a “vaccinal” effect may be an additional mechanism of action but to our knowledge there has been no direct evidence to support this in Rtx treated patients.Methods: To provide support for this hypothesis we examined lymphoma idiotype (Id) specific T-cell responses in peripheral blood mononuclear cells (PBMC) from three patients with relapsed FL. PBMC were obtained prior to and 4–6 weeks after the last of 4 weekly doses (375mg/m2 q week) of Rtx. A lymph node biopsy was obtained prior to Rtx to generate the patient's Id protein. Dendritic cells (DC) were generated from pre-Rtx PBMC and pulsed with;a.no protein (control);b.the patient's Id protein (Id); orc.an irrelevant (Irr) protein (Id from another patient).For patient 1, pre- and post-Rtx PBMC were stimulated with the DC for 1 week, while for patients 2 and 3, PBMC were stimulated for 1 week then re-stimulated for another week with fresh DC. Effectors were then assayed in triplicate for IFN-γ producing cells by Elispot. A second independent experiment was conducted in patients 2 and 3 (ie. this study describes data from 3 patients, 5 separate experiments).Results: Pre-Rtx: There was no consistent increase in the number of Id specific or Irr protein specific T-cells as compared to that of control T-cells. Post-Rtx: Whereas there was no consistent increase in the number of Irr protein specific T-cells as compared to that of control T-cells, in all three patients (including both replicates for patients 2 and 3) there was a consistent increase in the number of Id specific T-cells as compared to that of control T-cells. When composite data from all three patients were analyzed using a mixed ANOVA, the following p-values were obtained: Comparison Pre-Rtx Post-Rtx Control vs. Id 0.03 0.0003 Id vs. Irr 0.3 0.0005 Control vs. Irr 0.2 0.9ComparisonPre-RtxPost-RtxControl vs. Id0.030.0003Id vs. Irr0.30.0005Control vs. Irr0.20.9Conclusions: These data provide, to our knowledge, the first support for the hypothesis that Rtx treatment results in an increase in Id specific T-cell responses in FL patients. If indeed this is a mechanism of Rtx activity, then clinical strategies to augment this postulated vaccinal effect, such as anti-CTLA-4 antibodies or Id vaccination post Rtx, may further increase the clinical potential of this agent and change the way we develop combination therapies. Further study of immune responses in a larger number of FL patients treated with Rtx is warranted and ongoing.

Rituximab therapy in malignant lymphoma

Rituximab is the first monoclonal antibody to have been registered for the treatment of B-cell lymphomas. Randomized studies have demonstrated its activity in follicular lymphoma (FL), mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL) in untreated or relapsing patients. Non-comparative studies have shown an activity in all other lymphomas. Because of its high activity and low toxicity ratio, rituximab has transformed the outcome of patients with B-cell lymphoma. A combination of rituximab plus chemotherapy, rituximab+cyclophosphamide+doxorubicin+vincristine+prednisolone (R-CHOP), has the highest efficacy ever described with any chemotherapy in DLBCL and FL. Some patients are refractory to rituximab but the precise mechanisms of this refractoriness are not understood.

Monoclonal antibody as therapy for malignant lymphomas

Rituximab was the first monoclonal antibody to have been registered for the treatment of B-cell lymphomas. Randomized studies have demonstrated its activity in follicular lymphoma, mantle-cell lymphoma, and diffuse large B-cell lymphoma in untreated or relapsing patients. Because of its high activity and low toxicity ratio, rituximab has transformed the outcome of patients with B-cell lymphoma. A combination of rituximab plus chemotherapy, R-CHOP, has the highest efficacy ever described with any chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma. The role of radio-labelled antibodies is still to be defined. To cite this article: B. Coiffier, C. R. Biologies 329 (2006).

Evolving Role of Rituximab in the Treatment of Patients with Non-Hodgkin's Lymphoma

Rituximab is the first monoclonal antibody to have been registered for the treatment of B-cell lymphomas. Randomized studies have demonstrated its activity in follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma in untreated or relapsing patients. Rituximab has transformed the outcome of these patients because of its high activity and low toxicity. A combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, has the highest efficacy ever described with any chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma.

Fludarabine, Cyclophosphamide and Mitoxantrone for Untreated Follicular Lymphoma: a Report from the Non-Hodgkin's Lymphoma Co-operative Study Group

The aim of the study was to determine the safety and efficacy of the combination of fludarabine (FLU), cyclophosphamide (CY) and mitoxantrone (FLU/CY/MITO) in untreated follicular lymphomas (FL), Sixty patients with newly diagnosed stage II bulky to IV FL, median age 59 years (range 36-70), received FLU/CY/MITO regimen (FLU 25 mg/m2 days 1-3, CY 300 mg/m2 days 1-3, Mito 10 mg/m2 day 1). Patients received antibiotic oral prophylaxis during all treatments, and growth factors (G-CSF) when grade III granulocytopenia (WHO) occurred. The overall response rate was 87%: 46 patients achieved complete response (CR) (77%), 6 a partial response (10%) and 8 were non-responders. Fifty patients are surviving with a median observation time of 31 months. The 4-year estimated probability of overall survival and failure-free survival were 78.2% and 45% respectively. Thirty-five patients (58%) are still in CR. Sixty percent of patients experienced grade III-IV granulocytopenia. Two patients suffered grade III pulmonary infection and one grade III liver toxicity. In a subset of 46 patients, bcl-2 translocation was positive in bone marrow (BM) and/or peripheral blood (PB) of 36 patients. At the end of treatment, 25 of these patients had CR and 19 (76%) converted to polymerase chain reaction (PCR) negativity. FLU/CY/MITO regimen showed a high level of activity in follicular lymphoma. Toxicity, mainly hematological, was acceptable and the treatment was made feasible by the use of antibiotic prophylaxis and G-CSF. Significant non-hematological toxicities were seen, but no patients died. The conversion of bcl-2 from positive to negative by PCR in BM and/or PB suggests a possible role for this treatment in clearing minimal residual disease and improving patients' outcome.

Antibody-based therapy of non-Hodgkin's lymphoma

Monoclonal antibodies (mAb) have dramatically advanced our ability to treat non-Hodgkin's lymphoma (NHL), and there has been a virtual explosion of clinical data regarding their use. Rituximab is a humanized anti-CD20 mAb and has significant single agent activity in follicular lymphoma, and to a lesser extent in mantle-cell and diffuse large B-cell lymphoma (DLCL). Rituximab appears to have synergistic activity with cytotoxic chemotherapy and the combination has recently demonstrated improved rates of complete remission (CR) and overall survival in older patients with DLCL. Alemtuzumab (Campath-1H) is a humanized mAb targeting CD52 and has recently been approved in the USA for the treatment of fludarabine-refractory B-cell chronic lymphocytic leukaemia. Impressive activity has also been demonstrated in T-cell prolymphocytic leukaemia and mycosis fungoides. The radioconjugated anti-CD20 mAbs ibritumomab tiuxetan and I 131-tositumomab also have impressive clinical activity in low-grade B-cell NHL, and the former has demonstrated superior CR rates to rituximab. Myelosuppression is more significant however, and their place in the treatment algorithm remains to be clearly defined. Other immunotoxins (e.g. BL22) and mAb against alternate targets (e.g. epratuzumab, humanized anti-CD22) are in development.

The management of follicular lymphoma.

Follicular lymphoma is demonstrably incurable with conventional treatment. A number of strategies have prolonged the duration of remission. However, none have convincingly improved survival. The following new treatment modalities are currently being evaluated: Interferon, given either alone, in combination with conventional chemotherapy or as maintenance therapy certainly has activity in follicular lymphoma, although its precise role remains to be defined. Myelo-ablative therapy with autologous bone marrow transplantation, with or without in vitro treatment of the marrow, is showing encouraging preliminary results, although longer follow-up is required. The use of radiolabelled monoclonal antibodies is an exciting area of research, with responses being observed in patients in whom other treatments have failed. The purine analogues, for example fludarabine, are an interesting class of new compound. Once more, these are proving to be useful when other treatments have failed. These four treatment modalities are critically appraised in the present paper.

Mitotic counts in follicular lymphomas

Increased mitotic activity is associated with significantly shorter patient survival in some of the subtypes of diffuse non-Hodgkin's lymphomas. This study on 105 cases of follicular lymphoma was undertaken to determine the clinical significance of mitotic activity in follicular lymphomas. For each case, two pathologists independently counted mitotic figures in 20 random high-power fields. The difference of the average mitotic counts over 20 high-power fields for the two pathologists showed a Gaussian distribution with a median difference of -0.26 counts per high-power field and a standard error of 0.10 per cent. In 94 cases (91 per cent), the difference was less than two mitotic counts per high-power field, indicating good interobserver agreement. There was a statistically significant difference in mitotic counts between subtypes of follicular lymphoma as well as a gradient among subtypes, with the lowest mitotic activity in the poorly differentiated lymphocytic subtype and highest in the undifferentiated subtype. A multivariate statistical analysis of clinical and pathologic variables showed that mitotic figures were not of prognostic significance.