scholarly journals Prospects in the management of patients with follicular lymphoma beyond first-line therapy

Haematologica ◽  
2022 ◽  
Vol 107 (1) ◽  
pp. 19-34 ◽  
Author(s):  
David Qualls ◽  
Gilles Salles

The management of patients with relapsed or refractory follicular lymphoma has evolved markedly in the last decade, with the availability of new classes of agents (phosphoinositide 3-kinase inhibitors, immunomodulators, epigenetic therapies, and chimeric antigen receptor T cells) supplementing the multiple approaches already available (cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants). The diversity of clinical scenarios, the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies preclude firm recommendations and require personalized decisions. Patients with early progression require specific attention given the risk of histological transformation and their lower response to standard therapies. In sequencing therapies, one must consider prior treatment regimens and the potential need for future lines of therapy. Careful evaluation of risks and expected benefits of available options, which vary depending on location and socioeconomics, should be undertaken, and should incorporate the patient’s goals. Preserving quality of life for these patients is essential, given the likelihood of years to decades of survival and the possibility of multiple lines of therapy. The current landscape is likely to continue evolving rapidly with other effective agents emerging (notably bispecific antibodies and other targeted therapies), and multiple combinations being evaluated. It is hoped that new treatments under development will achieve longer progression-free intervals and minimize toxicity. A better understanding of disease biology and the mechanisms of these different agents should provide further insights to select the optimal therapy at each stage of disease.

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 194-199 ◽  
Author(s):  
Christopher R. Flowers ◽  
John P. Leonard ◽  
Loretta J. Nastoupil

AbstractFollicular lymphoma (FL) remains a lymphoma subtype that is remarkably sensitive to immunotherapy-based treatment strategies. Anti-CD20 antibody therapy administered as a single agent and in combination as a first-line treatment and at relapse continues to be the most broadly used therapy for this disease. Autologous and allogeneic stem cell transplantation provide meaningful durable remissions for patients with FL. However, identifying the most suitable patients and the optimal timing for these approaches has become increasingly challenging with the advent of novel therapies. Lenalidomide and phosphatidylinositol 3-kinase inhibitors are emerging as agents that can be applied in the relapsed setting. Other immunotherapy approaches, including checkpoint inhibitors and chimeric antigen receptor T cells, appear promising but remain experimental. Utilization of all forms of immunotherapy requires careful consideration of the unique toxicities associated with these agents and the means to mitigate them by selection of appropriate patients, optimal timing, and the use of supportive care.


2021 ◽  
Vol 14 (2) ◽  
pp. 80
Author(s):  
Mei Elsayed ◽  
Petros Christopoulos

Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK+ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK+ tumors.


2016 ◽  
Vol 8 ◽  
pp. 2016061 ◽  
Author(s):  
Giuseppe Rossi ◽  
Antonella Anastasia

Follicular lymphoma(FL) is the most common indolent non-Hodgkin lymphoma and constitutes 15% to 30% of lymphoma diagnoses. The natural history of the disease is characterized by recurrent relapses and progressively shorter remissions with a median survival of 10yrs. The impossibility of a chieving a definite cure, have prompted investigations into the possible role of more effective and less toxic strategies with innovative therapeutic agents.  Recently Casulo et al demonstrated that approximately 20% of patients with FL actually relapse within 2 years after achieving remission with R-CHOP and have a poor prognosis. It is conceivable that this particularly chemoresistant population would benefit from specifically targeting the biologic and genetic factors that likely contribute to their poor prognosis.Evolving strategies for difficult to treat FL patients have recently considered  immunomodulatory agents, new monoclonal antibodies as well as drugs targeting selective intracellular pathways. The importance of targeting the microenvironment together with the malignant FL cell has been particularly underscored. We review the most promising approaches, such as the combination of anti-CD20 antibodies with immunomodulatory drugs (Lenalidomide), with mAbs directed against other surface antigens such as CD22 and CD23 (epratuzumab, lumiliximab), with immunomodulatory antibodies such as PD-1, or with inhibitors of key steps in the B-cell receptor pathway signaling such as PI3K inibithors(idelalisib, duvelisib). Another highly attractive approach is the application of the bi-specific T-cell engaging (BiTE) antibody blinatumomab which targets both CD19 and CD3 antigens. Moreover, we highlight the potential of these therapies,  taking into account their toxicity. Of course we must wait for Phase III trials results to confirm the benefit of these new treatment strategies toward a new era of chemotherapy-free treatment for follicular lymphoma.


Pituitary ◽  
2019 ◽  
Vol 23 (1) ◽  
pp. 27-37 ◽  
Author(s):  
P. Souteiro ◽  
N. Karavitaki

Abstract Consensus guidelines recommend dopamine agonists (DAs) as the mainstay treatment for prolactinomas. In most patients, DAs achieve tumor shrinkage and normoprolactinemia at well tolerated doses. However, primary or, less often, secondary resistance to DAs may be also encountered representing challenging clinical scenarios. This is particularly true for aggressive prolactinomas in which surgery and radiotherapy may not achieve tumor control. In these cases, alternative medical treatments have been considered but data on their efficacy should be interpreted within the constraints of publication bias and of lack of relevant clinical trials. The limited reports on somatostatin analogues have shown conflicting results, but cases with optimal outcomes have been documented. Data on estrogen modulators and metformin are scarce and their usefulness remains to be evaluated. In many aggressive lactotroph tumors, temozolomide has demonstrated optimal outcomes, whereas for other cytotoxic agents, tyrosine kinase inhibitors and for inhibitors of mammalian target of rapamycin (mTOR), higher quality evidence is needed. Finally, promising preliminary results from in vitro and animal reports need to be further assessed and, if appropriate, translated in human studies.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3330-3330 ◽  
Author(s):  
Josiah N. Orina ◽  
Christopher R. Flowers

Abstract Background: Current guidelines offer numerous options for initiating therapy in patients with untreated, advanced stage follicular lymphoma (FL). Selecting among these options that include watchful waiting, single-agent and combination chemotherapy, monoclonal antibodies, and radioimmunotherapy, remains challenging. Recent data suggest that chemotherapy combined with a monoclonal antibody may alter patterns of relapse and overall survival for pts with FL (Fisher, Blood 2004). While rituximab (R) chemotherapy combinations have become commonly used for untreated pts with FL, to date, the optimal first-line therapy remains undefined. To address this issue, we updated a systematic literature review and performed a meta-analysis of first-line therapy for untreated FL that examined the effect of various chemotherapy regimens combined with R on response rates and survival in patients with untreated FL. Methods: The comprehensive systematic review included searches the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 1, 2003), MEDLINE (1/1996–6/2006), EMBASE (1/1980–7/2006), American Society of Hematology Annual Meeting abstracts (2002–2005), and American Society of Clinical Oncology Annual Meeting abstracts (1995–2006). Each database was searched using combinations of the term follicular lymphoma and the terms for medications and treatment regimens. Inclusion criteria for studies were as follows: 1) Inclusion of patients with untreated stage III/IV FL grades 1, 2, or 3; 2) Intervention with chemotherapy and/or immunotherapy, radioimmunotherapy, or watchful waiting; 3) Reporting in English of the following treatment outcome measures specifically for patients with FL: CR/CR-unconfirmed, overall response rate (OR), and at least one form of survival data. Abstracts subsequently published as papers were excluded. Extracted data included pre-treatment disease status, treatment regimen, median follow-up time, progression free survival, overall survival, CR and OR. The following treatment strategies from peer-review publications were analyzed: single agent R, R-CVP, R-CHOP, and fludarabine-combinations with R (R-Fcom). In meta-analyses of selected studies, we utilized the Mantel-Haenszel (fixed effects model) and DerSimonain and Laird (random effects) methods to calculate the risk difference comparing treatment regimens’ CR/CRu to the spontaneous CR in patients undergoing watchful waiting (4.6%; Ardeshna et al. Lancet, 2003). Results: In total, over 3135 abstracts were reviewed to identify 11 studies meeting the inclusion criteria for this analysis. These studies included data from 3144 patients. Only one study presenting CR data for R-CVP (36%, 95% confidence interval: 28%–44%) met inclusion criteria. The meta-analyses estimated the CR rate associated with single-agent R to be 30% (95% CI: 20%–40%), R-CHOP to be 62% (30%–94%), and R-Fcom to be 85% (76%–94%) (random effects; see Figure). Conclusions: R-CHOP and R-fludarabine combinations appear to produce the highest CR rates for untreated pts with FL. Meta-analysis can aid clinicians in therapeutic decision making as they weight the risks and benefits of various regimens for newly diagnosed pts. Figure Figure


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1395-1395
Author(s):  
Antti Harjunpää ◽  
Matti Nykter ◽  
Outi Monni ◽  
Marja-Liisa Karjalainen-Lindsberg ◽  
Samuli Hemmer ◽  
...  

Abstract The anti-CD20 monoclonal antibody rituximab has been extensively evaluated for treatment of follicular lymphoma (FL) and is now an integral component of many treatment strategies. However, it is not known when and how to use this combination modality best in the overall treatment course of FL patients. Here we have analyzed the pattern of gene expression in lymph nodes from 28 FL patients who received rituximab in combination with chemotherapy. We demonstrate a novel feature selection method, in which genes whose expression correlates with treatment outcome are devided into groups based on similar expression patterns. By selecting representatives from these groups we built a three-gene predictor (for example RRAD, MGC5254, MARCO) which turned out to be successful in classifying all 28 samples correctly with respect to the responders versus nonresponders distinction. A similar four-gene predictor (for example USP9Y, CUL-4B, NSFS/REST, MADH) correctly classified the responding patients into two subgroups with very different event-free survival rates at the median follow up of 21 months (median not reached vs. 15 months, p<0.0001). The latter predictor also efficiently delineated patients within specific FLIPI risk groups. Our data demonstrate the ability of these microarray-based predictors to classify FL patients treated with rituximab and chemotherapy to subgroups with significantly distinct outcomes.


2006 ◽  
Vol 24 (20) ◽  
pp. 3282-3292 ◽  
Author(s):  
Wolfgang A. Weber

Positron emission tomography (PET) allows noninvasive, quantitative studies of various biologic processes in the tumor tissue. By using PET, investigators can study the pharmacokinetics of anticancer drugs, identify various therapeutic targets and monitor the inhibition of these targets during therapy. Furthermore, PET provides various markers to assess tumor response early in the course of therapy. A significant number of studies have now shown that changes in tumor glucose utilization during the first weeks of chemotherapy are significantly correlated with patient outcome. These data suggest that PET may be used as a sensitive test to assess the activity of new cytotoxic agents in phase II studies. Furthermore, early identification of nonresponding tumors provides the opportunity to adjust treatment regimens according to the individual chemosensitivity of the tumor tissue. However, further prospective and randomized validation of PET is still required before PET controlled chemotherapy can be used in clinical practice.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19089-e19089
Author(s):  
Jordi Remon ◽  
Teresa Moran ◽  
Diego Alcaraz ◽  
Laia Capdevila ◽  
Rut Porta ◽  
...  

e19089 Background: Different therapeutic approaches have been used in the clinical setting in NSCLC p harbouring EGFR mutations progressing to rTKI, although the standard of care in this situation is still not well established. Methods: A multi-institutional database from four different centers in Spain was review to identify EGFR mut p with acquired resistance to rTKI in order to evaluate the therapeutic strategies after rTKI failure and the effect on the post-progression survival (PPS) of these treatments. Results: 41 p with acquired resistance to rTKI were identified: 63% female; median (m) age 62 ±11 yrs; 95% Caucasian; del19 76%, never or light former smokers 100%; 90.2% adenocarcinomas; 51 % received TKI as first line therapy; 85% were initial stage IV .mPFS for the rTKI was 8.4 months (mo) and mOS was 29.7 mo for the entire population. P were treated with a median of 2 therapeutic strategies after the rTKI failure. 6 therapeutic strategies have been identified. As immediate approach, 16 p were switched to chemotherapy (CT) with a mPPS of 3 mo. 9 p were switched to an irreversible TKI obtaining a mPPS of 3.9 mo. rTKI plus other drug was maintained in 11 p: rTKI plus CT in 9 p with a mPPS of 4 mo and rTKI plus other drug different to CT in 2 with a mPPS of 2 mo. Despite the progression, rTKI was maintained in 2 p considered slow progressors and local therapy, in addition to the rTKI, was administered in 3 p with oligoM1progressive disease obtaining a mPPS of 1.4 and 36 mo, respectively. 8 p were treated sequentially with ≥5 strategies. These p attained a mOS of 27.7 mo. Conclusions: The combination of different strategies when treating EGFR mut p after rTKI failure may impact the survival especially when p are candidates to receive some of this treatments sequentially. These strategies may reflect different subsets of EGFR mut disease.


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