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Immunopathogenesis Advances in Diabetes and Lymphomas

Larry H Bernstein, MD, FCAP, Curator

LPBI

 

 

 Science team says they’ve taken another step toward a potential cure for diabetes

Wednesday, January 27, 2016 | By John Carroll
Building on years of work on developing new insulin-producing cells that could one day control glucose levels and cure diabetes, a group of investigators led by scientists at MIT and Boston Children’s Hospital say they’ve developed a promising new gel capsule that protected the cells from an immune system assault.

Dr. Jose Oberholzer, a professor of bioengineering at the University of Illinois at Chicago, tested a variety of chemically modified alginate hydrogel spheres to see which ones would be best at protecting the islet cells created from human stem cells.

The team concluded that 1.5-millimeter spheres of triazole-thiomorphine dioxide (TMTD) alginate were best at protecting the cells and allowing insulin to seep out without spurring an errant immune system attack or the development of scar tissue–two key threats to making this work in humans.

They maintained healthy glucose levels in the rodents for 174 days, the equivalent to decades for humans.

“While this is a very promising step towards an eventual cure for diabetes, a lot more testing is needed to ensure that the islet cells don’t de-differentiate back toward their stem-cell states or become cancerous,” said Oberholzer.

Millions of diabetics have effectively controlled the chronic disease with existing therapies, but there’s still a huge unmet medical need to consider. While diabetes companies like Novo ($NVO) like to cite the fact that a third of diabetics have the disease under control, a third are on meds but don’t control it well and a third haven’t been diagnosed. An actual cure for the disease, which has been growing by leaps and bounds all over the world, would be revolutionary.

Their study was published in Nature Medicine.

– here’s the release
– get the journal abstract

 

Long-term glycemic control using polymer-encapsulated human stem cell–derived beta cells in immune-competent mice

Arturo J Vegas, Omid Veiseh, Mads Gürtler,…, Robert Langer & Daniel G Anderson

Nature Medicine (2016)   http://dx.doi.org:/10.1038/nm.4030

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes1. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically2, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue3. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy4. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier56. However, clinical implementation has been challenging because of host immune responses to the implant materials7. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells. SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.

Subject terms: Regenerative medicine  Type 1 diabetes

Figure 1: SC-β cells encapsulated with TMTD alginate sustain normoglycemia in STZ-treated immune-competent C57BL/6J mice.close

(a) Top, schematic representation of the last three stages of differentiation of human embryonic stem cells to SC-β cells. Stage 4 cells (pancreatic progenitors 2) co-express pancreatic and duodenal homeobox 1 (PDX-1) and NK6 homeobox 1…

 

Potential Cure for Diabetes Discovered  
http://www.rdmag.com/news/2016/01/potential-cure-diabetes-discovered   01/27/2016

Two new scientific papers published on Monday demonstrated tools that could result in potential therapies for patients diagnosed with type 1 diabetes, a condition in which the immune system limits the production of insulin, typically in adolescents.  See —

Bubble Technique Could Create Type 1 Diabetes Therapy

http://www.dddmag.com/news/2016/01/bubble-technique-could-create-type-1-diabetes-therapy

Two new scientific papers published on Monday demonstrated tools that could result in potential therapies for patients diagnosed with type 1 diabetes, a condition in which the immune system limits the production of insulin, typically in adolescents.

Previous treatments for this disease have involved injecting beta cells from dead donors into patients to help their pancreas generate healthy-insulin cells, writes STAT. However, this method has resulted in the immune system targeting these new cells as “foreign” so transplant recipients have had to take immune-suppressing medications for the rest of their lives.

The first paper published in the journal Nature Biotechnology explained how scientists analyzed a seaweed extract called alginate to gauge its effectiveness in supporting the flow of sugar and insulin between cells and the body. An estimated 774 variations were tested in mice and monkeys in which results indicated only a handful could reduce the body’s response to foreign invaders, explains STAT.

The other paper in the journal Nature Medicine detailed a process where scientists developed small capsules infused with alginate and embryonic stem cells. A six-month observation period revealed this “protective bubble” technique “began to produce insulin in response to blood glucose levels” after transplantation in mice subjects with a condition similar to type 1 diabetes, reports Gizmodo.

Essentially, this cured the mice of their diabetes, and the beta cells worked as well as the body’s own cells, according to the researchers. Human trials could still be a few years away, but this experiment could yield a safer alternative to insulin injections.

 

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates

Arturo J Vegas, Omid Veiseh, Joshua C Doloff, et al.

Nature Biotechnology (2016)    http://dx.doi.org:/10.1038/nbt.3462

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient1, 2, 3, 4, 5, 6. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.

 

Video 1: Intravital imaging of 300 μm SLG20 microcapsules.

Video 2: Intravital imaging of 300 μm Z2-Y12 microcapsules.

Video 3: NHP Laparoscopic procedure for the retrieval of Z2-Y12 spheres.

 

Clinical Focus on Follicular Lymphoma: CAR T-Cells Active in Relapsed Blood Cancers

MedPage Today

CAR T-Cells Active in Relapsed Blood Cancers

Complete responses in half of patients

by Charles Bankhead

Patients with relapsed and refractory B-cell malignancies have responded to treatment with modified T-cells added to conventional chemotherapy, data from an ongoing Swedish study showed.

Six of the first 11 evaluable patients achieved complete responses with increasing doses of chimeric antigen receptor (CAR)-modified T-cells that target the CD19 antigen, although two subsequently relapsed.

Five of the six responding patients received preconditioning chemotherapy the day before CAR T-cell infusion, in addition to chemotherapy administered up to 90 days before T-cell infusion to reduce tumor-cell burden. The remaining five patients received only the earlier chemotherapy, according to a presentation at the inaugural International Cancer Immunotherapy Conference in New York City.

“The complete responses in lymphoma patients despite the fact that they received only low doses of preconditioning compared with other published data surprised us,” Angelica Loskog, PhD, of Uppsala University in Sweden, said in a statement. “The strategy of both providing tumor-reductive chemotherapy for weeks prior to CAR T-cell infusion combined with preconditioning just before CAR T-cell infusion seems to offer promise.

CAR T-cells have demonstrated activity in a variety of studies involving patients with B-cell malignancies. Much of the work has focused on patients with leukemia, including trials in the U.S. B-cell lymphomas have proven more difficult to treat with CAR T-cells because the diseases are associated with higher concentration of immunosuppressive cells that can inhibit CAR T-cell activity, said Loskog. Moreover, blood-vessel abnormalities and accumulation of fibrotic tissue can hinder tumor penetration by therapeutic T-cells.

Each laboratory has its own process for modifying T-cells. Loskog and colleagues in Sweden and at Baylor College of Medicine in Houston have developed third-generation CAR T-cells that contain signaling domains for CD28 and 4-1BB, which act as co-stimulatory molecules. In preclinical models, third-generation CAR T-cells have demonstrated increased activation and proliferation in response to antigen challenge. Additionally, they have chosen to experiment with tumor burden-reducing chemotherapy, a preconditioning chemotherapy to counter the higher immunosuppressive cell count in lymphoma patients.

Loskog reported details of an ongoing phase I/IIa clinical trial involving patients with relapsed or refractory CD19-positive B-cell malignancies. Altogether, investigators have treated 12 patients with increasing doses (2 x 107 to 2 x 108 cells/m2) of CAR T-cells. One patient (with mixed follicular/Burkitt lymphoma) has yet to be evaluated for response. The remaining 11 included three patients with diffuse large B-cell lymphoma (DLBCL), one with follicular lymphoma transformed to DLBCL, two with chronic lymphocytic leukemia, two with mantle cell lymphoma, and three with acute lymphoblastic leukemia.

All of the patients with lymphoma received standard tumor cell-reducing chemotherapy, beginning 3 to 90 days before administration of CAR T-cells. Beginning with the sixth patient in the cohort, patients also received preconditioning chemotherapy (cyclophosphamide/fludarabine) 1 to 2 days before T-cell infusion to reduce the number and activity of immunosuppressive cells.

Cytokine release syndrome is a common effect of CAR T-cell therapy and occurred in several patients treated. In general, the syndrome has been manageable and has not interfered with treatment or response to the modified T-cells.

On the basis of the data produced thus far, the investigators have proceeded with patient evaluation and enrollment. They have already begun cell production for the next patient that will be treated with autologous CAR T-cells.

Although laboratories have their own cell production techniques, the treatment strategy has broad applicability to the treatment of B-cell malignancies, said Loskog.

“The results using different CARs and different techniques for manufacturing them is very similar in the clinic, in terms of initial complete response,” she told MedPage Today. “By using 4-1BB as a co-stimulator in the CAR intracellular region, it seems possible to achieve long-term complete responses in some patients. However, preconditioning of the patients with chemotherapy to reduce the regulatory immune cells seems crucial for effect.”

In an effort to manage the effect of patients’ immunosuppressive cells, the investigators have begun studying each the immune profile before and after treatment. Preliminary results suggest that the population of immunosuppressive cells increases over time, which has the potential to interfere with CAR T-cell responses.

“Especially for lymphoma, it may be crucial to deplete such cells prior to CAR infusion,” said Loskog. “It may even be necessary with supportive treatment for some time after CAR T-cell infusion. A supportive treatment needs to specifically regulate the suppressive cells while sparing the effect of CARs.”

The immunotherapy conference is jointly sponsored by the American Association for Cancer Research, the Cancer Research Institute, the Association for Cancer Immunotherapy, and the European Academy of Tumor Immunology.

 

PET-CT Best for FL Response Assessment

PET-CT associated with better progression-free and overall survival rates in follicular lymphoma.

Kay Jackson

PET-CT (PET) rather than contrast-enhanced CT scanning should be considered the new gold standard for response assessment after first-line rituximab therapy for high-tumor burden follicular lymphoma (FL), a pooled analysis of a central review in three multicenter studies indicated.

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Leaders in the CAR-T Field Are Proceeding With Cautious Hope

Reporter: Stephen J. Williams, Ph.D.

It wasn’t a long time ago, in fact the May 26, 2014 Cover Story in Forbes entitled “Is This How We’ll Cure Cancer” with cover photo of Novartis CEO Joseph Jimenez and subtitle “Will This man Cure Cancer?” highlighted the promise of CAR-T therapy as the ‘magic bullet’ therapy which will eventually cure all cancer. However, over the years, the pioneers of such therapy, while offering impressive clinical results, caution not to get to eager in calling CAR-T as the end-all-be-all cure but insist there are many issues that need be resolved.

The Allogenic Approach

In an interview for LabBiotech.eu Phillip Hemme had a discussion (and wonderful writeup) with André Choulika, the CEO of the French CAR-T miracle Cellectis on the current state of CAR-T therapy for cancer. Below is the interview in full as ther ae multiple important point Dr. Choulika mentioned, including how much is needed to be done in the field.

Cellectis’ CEO: “I’m just trying to be realistic, CAR-T is not THE miracle cure for Cancer”

 

 

Cellectis

CAR-T is solidifying in everybody’s mind as the next revolution in Cancer treatment. But there is still a lot to do…That’s basically what came out from my discussion with André Choulika, the CEO of the French CAR-T miracle Cellectis.

Cellectis is probably the most successful Biotech in France. It was founded in 1999 by Choulika himself (not alone though), following the discovery of meganucleases ability to change gene editing. Today, Cellectis is a well-known Biotech company counting over 100 employees end of October and having a market cap north of 1 Billion euros.

The company is now focused on the development of allogenic CAR-T (from generic donors  – i.e. not from the patient themself). With these universal CAR-T candidates (UCARTs). Cellectis has signed a massive partnership with the French pharma Servier, as well as Pfizer (which owns 8% of Cellectis), and has just announced two big milestones for the company within the last few weeks.

It is now able to produce it’s allogenic CAR-T in a GMP settings and it releases results from the “miracle” treatment of a 11-month old girl from the UK with multi-resistant leukemia.

 

Let’s start directly with the latest news…People seemed over-enthusiastic about UCART19…even the New York Times wrote about it. What do you think?

It’s a great news for Cellectis even though it’s still a very early result, in a single patient only. What’s important for us is that the first human patient received our treatment without showing any adverse effects (such as no cytokinetic storm) and our CAR-T cells were still active in the body 3 months after the injections.

Now, we have to expand the clinical trials to several patients and showing data from a cohort of patients. We are now on track to file the clinical trial application by the end of the year.

Your approach in the CAR-T is pretty unique. You are using donor’s cells to treat many different patients, whereas most CAR-T approaches are autologous (i.e. engineered the patient’s own cells).  Is the future in CAR-T the allogenic approach alone?

When we started to move into the CAR-T field we were pretty reluctant because there are not many examples of commercial success in the field yet. But CAR-T has still attracted many big players such as Novartis, Celgene, Juno or Kite. These each have a strong involvement in making autologous therapies work commercially (Celgene especially, which makes most of its revenue from groundbreaking and pricey cancer drugs).

On our side, we want to make this therapy accessible to a larger population and have good market access at the end. We have already pretty good reason to think it could work out well for us. We’ll see though…

Comment: Reuters published a report a few weeks ago estimating the cost of autologous CAR-T could be above $450K per treatment, which would make it economically not realistic for the healthcare payers.

CAR-T seems to be extremely hype right now. At BIO-Europe 2015, I had the impression everybody was talking about CAR-T. Do you think it could have the same impact as monoclonal antibodies?

What’s interesting with CAR-T is that you can target cells which expresses less receptors (10k receptors instead of 100k for monoclonal antibodies). This increases the targets for CAR-T and the possibilities linked.

But there are also downsides. Tissues with low expressions can become targets too and CAR-T cells would start attacking healthy cells.

People should not overemphasise CAR-T. We are still at the beginning of the beginning of this technology. And it will probably have to be combined with surgery or checkpoint inhibitors.

 

You seem pessimistic about CAR-T…?

I am just trying to be more realistic, even though I am super positive about the technology. It will bring something really great to Haematology field, but is not a cure for Cancer. It’s more of a long-haul race in the right direction as opposed to fast results, and we expect great things perhaps 20 years down the line as opposed to 2016.

But yes, it will probably not be the miracle product some people are talking about.

As for every early technology, there are many challenges associated with its development. What are the main ones worth discussing?

I would say you have four main challenges…

The administration of the cells will be challenging. We have to find way of injecting repeated doses of the product (to ensure the therapy is fully effective seeing as CAR-T cells have a limited lifespan). This is difficult because of immunogenicty against the therapy.

Secondly, combination will play an essential role too and checkpoint inhibitors should be involved.

The last two are linked to the targets.

As I mentioned before, CAR-T can be too sensitive and one way to control that would be to induce “logic gates” where the cells would only act if a combination of receptors would be present. The last challenge is to find other antigens.

Most of the CAR-T cells today target the same antigen: CD19+. We should find new antigens and many companies are on the track, including us.

 

CD19 CART

An anti-CD19 CAR-expressing T cell recognizing a CD19+ (Source: Kochenderfer et al., Nature Reviews Clinical Oncology 10, 267-276, doi: 10.1038/nrclinonc.2013.46)

Autologous CART therapy

Dr. Carl June of University of Pennsylvania, who has helped pioneer the field of CAR-T therapy for leukemia, has also been cautiously hopeful on the progress of the therapy. In his 2015 AACR National Meeting address, he highlighted some achievements they had with CAR-T therapy in both hematologic as well as solid tumors however it was stressed that there is much work to do with regards to optimization of the system, characterization of new tumor antigens for diverse tumor types, as well as the need to develop optimal treatment strategies to mitigate toxicities. Indeed many of the pioneers in the field have been proactive in helping to develop pharmacovigilance, safety, and regulatory strategies (highlighted in a post found here: NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee and mitigating toxicities in a post Steroids, Inflammation, and CAR-T Therapy) and much credit should be given to these researchers.

https://youtu.be/1sA_oz_1P5E

Cancer Research Institute’s Breakthroughs in Cancer Immunotherapy Webinar Series are offered free to the public and feature informative updates from leaders in cancer immunotherapy, followed by a moderated Q&A. On June 10, 2013, Carl H. June, M.D., a specialist in T cell biology and lymphocyte activation at the Perelman School of Medicine, University of Pennsylvania, discussed his groundbreaking work that has led to remarkable remissions of advanced cancer. He focused on recent and ongoing successes in developing treatments with T cells that have been genetically engineered to target cancer. Called chimeric antigen receptor T cells (CAR T cells), these modified immune cells have proven effective at eliminating cancer in some patients, and offer great hope for this emerging strategy in cancer immunotherapy. For more information on this webinar, or to register for upcoming webinars, please visit www.cancerresearch.org/webinars.

Below are reports from the 2015 American Society of Hematology Conference by Novartis on results from CTL109 CART therapy trials. One trial is on response rate in B-cell lymphomas and follicular cell lymphomas while the second report is ongoing trial results in childhood refractory ALL, both conducted at University of Pennsylvania.

Novartis presents response rate data for CART therapy CTL019 in lymphoma

(Ref: Global Post, NASDAQ, PR Newswire)

posted on FirstWorldPharma.com December 6th, 2015

By: Matthew Dennis

Novartis announced Sunday data from an ongoing Phase IIa study demonstrating that the experimental chimaeric antigen receptor T-cell (CART) therapy CTL019 led to an overall response rate (ORR) at three months of 47 percent in adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and an ORR of 73 percent in adults with follicular lymphoma. The results of the trial were presented at the American Society of Hematology annual meeting.

Findings from the study, which was conducted by the University of Pennsylvania’s Perelman School of Medicine, include 15 adults with DLBCL and 11 with follicular lymphoma who were evaluable for response. Results showed that three patients with DLBCL who achieved a partial response (PR) to treatment at three months converted to complete response (CR) by six months. In addition, three patients with follicular lymphoma who achieved a PR at three months converted to CR by six months.

Novartis added that one DLBCL patient with a PR at three months experienced disease progression at six months after treatment. Further, one follicular lymphoma patient with a PR at three months who remained in PR at nine months experienced disease progression at approximately 12 months after treatment. The company indicated that median progression-free survival was 11.9 months for patients with follicular lymphoma and 3 months for those with DLBCL.

In the study, four patients developed cytokine release syndrome (CRS) of grade 3 or higher. Novartis noted that during CRS, patients typically experience varying degrees of influenza-like symptoms with high fevers, nausea, muscle pain, and in some cases, low blood pressure and breathing difficulties. Meanwhile, neurologic toxicity occurred in two patients in the trial, including one grade three episode of delirium and one possibly related grade five encephalopathy.

“These data add to the growing body of clinical evidence on CTL019 and illustrate its potential benefit in the treatment of relapsed and refractory non-Hodgkin lymphoma,” commented lead investigator Stephen Schuster. Novartis indicated that the findings keep CTL019 on track for submission to the FDA in 2017. Usman Azam, global head of Novartis’ cell and gene therapies unit, said “we remain consistent again with the data set.”

“It’s an attractive population, it’s a population that continues to have a huge unmet need, it’s a cornerstone of our investments,” Azam remarked. Analysts expect CART therapies, once approved, to cost up to $450 000 per patient. Novartis acknowledged that prices will be high, but declined to give further details. “With any disruptive innovation that comes, initially, cost of goods is very challenging,” Azam said, adding “as time goes on, and more patients are treated, we will simplify that cost base.”

Source: http://www.firstwordpharma.com/node/1338217?tsid=28&region_id=2#axzz3tfDVaT1f

 

 

Novartis AG (NVS)’s Experimental Therapy Wipes Out Blood Cancer in 93 Percent of Patients

Reported in Biospace.com (for full article see here)

Novaritis and University of Pennsylvania reported results of the CTL019 CART trials for the treatment of children with relapsed/refractory acute lymphoblastic leukemia at the 2015 Annual Hemotologic Society Meeting. 55 of 59 patients, or 93 percent, experienced complete remissions with CTL019. The study did show that at the end of one year, 55 percent of patients had a remission-free survival rate and that 18 patients continued to show complete remission following one year

 

Other posts on the Open Access Journal on CAR-T therapy include

 

CAR-T therapy in leukemia

Steroids, Inflammation, and CAR-T Therapy

NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

 

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Management of Follicular Lymphoma

Curator: Larry H. Bernstein, MD, FCAP

 

Targeted Approaches to the Management of Follicular Lymphoma  

By Chaitra Ujjani, MD

http://www.cancernetwork.com/oncology-journal/targeted-approaches-management-follicular-lymphoma

 

Despite high rates of response to initial chemoimmunotherapy, patients with follicular lymphoma experience frequent relapses, and better treatment options are needed. Several novel biologic agents have been developed based on a greater understanding of the intrinsic factors driving the development of this heterogeneous disease. Such therapies target extracellular surface proteins and intracellular signaling pathways, as well as manipulate and engage the tumor microenvironment. Many of these agents have shown great promise in early-phase studies and are the focus of ongoing clinical investigations.

 

Introduction As the second most common form of non-Hodgkin lymphoma (NHL), follicular lymphoma affects thousands of new patients in the United States each year. Although follicular lymphoma is considered an indolent disease, its clinical course is highly variable. Asymptomatic patients with low tumor burden can be monitored closely with the “watch and wait” strategy, given that the early intervention of chemotherapy or immunotherapy has not demonstrated a survival benefit.[1,2] The most widely accepted indications for treatment are one or more of the following criteria from the Groupe d’Etude des Lymphomes Folliculaires (GELF): a single lesion > 7 cm, three nodal sites > 3 cm, splenomegaly, effusions, threat or evidence of organ compression, or constitutional symptoms.[3] Whereas patients with limited-stage disease have several treatment options—including single-agent rituximab, radiation, and chemoimmunotherapy, those with advanced-stage disease typically receive chemoimmunotherapy.[4,5] Both the German Study Group Indolent Lymphomas (StiL) NHL-2 study and the pharmaceutical company–sponsored Bendamustine Rituximab Investigational Non-Hodgkin’s Trial (BRIGHT) have established the front-line role of combination therapy with bendamustine and rituximab in the treatment of follicular lymphoma, based on comparable efficacy and better tolerability than standard regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).[6,7] Despite high response rates with initial therapy, follicular lymphoma is characterized by frequent relapses, and patients need improved treatment options.

Oncology (Williston Park). 29(10):760-768.

 

http://www.cancernetwork.com/sites/default/files/styles/figures_diagrams/public/figures_diagrams/1510ujjaniTable.png

Table: Targeted Therapies in Development and FDA-Approved for the Treatment of Follicular Lymphomas

 

Since the discovery of rituximab, there has been significant innovation in drug development, based on a greater understanding of the pathogenesis of the disease. The multistep process leading to follicular lymphoma is theorized to begin with an initial genetic insult, the hallmark t(14;18) translocation, which results in overexpression of the anti-apoptotic B-cell lymphoma protein, BCL-2.[8] This translocation is not the sole factor in malignant transformation, as it is a naturally occurring anomaly, often identified in healthy individuals. Furthermore, preclinical studies have indicated a positive correlation between increasing numbers of genetic alterations and the progression from follicular lymphoma in situ to grade 3A follicular lymphoma.[9] The B-cell receptor is a critical cellular factor in the development of the disease. Its active tonic signaling leads to recruitment of the spleen tyrosine kinase (SYK) and activation of multiple downstream pathways, including phosphatidylinositol 3-kinase (PI3K), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and mitogen-activated protein kinase (MAPK). Activation of these pathways ultimately results in the maturation, proliferation, and survival of malignant lymphocytes.[10] Other key components include immune cells such as T cells, dendritic cells, and reticular cells, which infiltrate among the centrocytes.[11] In addition to stimulating the B-cell receptor, these immune cells induce exhaustion of cytotoxic T cells and allow for T-cell evasion via disruption of synapses and secretion of interleukin-12.[12] Expression of the inhibitory receptor programmed cell death 1 (PD-1) is another contributing factor, as its presence is believed to affect the ability of T cells to mount appropriate antitumor responses.[13] Several novel therapies have been developed to target these various aspects of the disease in the hope of identifying more effective, yet tolerable, treatment options for patients with follicular lymphoma. (See the Table for a summary of therapies approved and in development for treatment of follicular lymphoma.)

 

Since the approval of rituximab, there has been significant investigation into the development of a superior anti-CD20 monoclonal antibody. Second- and third-generation versions vary in their structures and mechanisms of action. Two anti-CD20 antibodies, ofatumumab and obinutuzumab, have been approved by the US Food and Drug Administration (FDA) for indications in chronic lymphocytic leukemia (CLL). Ofatumumab, a type I human monoclonal antibody, was initially approved for patients whose disease is refractory to fludarabine and alemtuzumab.[14] Obinutuzumab was approved in combination with chlorambucil for patients with preexisting comorbidities that preclude conventional chemoimmunotherapy.[15] Although designed to induce stronger complement-dependent cytotoxicity than rituximab, ofatumumab demonstrated minimal activity in rituximab-refractory follicular lymphoma (overall response rate [ORR], 10% to 13%; median progression-free survival [PFS], 5.8 months).[16] In phase II trials of ofatumumab in combination with chemotherapy, including bendamustine and CHOP, results appeared comparable to those achieved with rituximab-based regimens, although no direct comparisons have been made.[17,18]

Obinutuzumab, a type II glycoengineered humanized antibody, is further in development for use in NHL. This agent, which works primarily by triggering antibody-dependent cellular cytotoxicity (ADCC) and apoptosis, has demonstrated superiority to rituximab in preclinical studies, including those employing whole blood B cell–depletion assays, human lymphoma xenograft mice models, and nonhuman primates.[19] When compared with rituximab in patients with indolent B-cell NHL, obinutuzumab produced a higher ORR by independent radiology review (45% vs 27%; P = .01); however, complete response (CR) and PFS rates were similar.[20] Like ofatumumab, treatment with obinutuzumab is associated with a higher rate of infusion-related reactions than rituximab (grade 1–4, 72% vs 49%; and grade 3/4, 11% vs 5%, respectively). In contrast to ofatumumab, it has efficacy in rituximab-refractory indolent NHL, producing an ORR of 50% and median PFS of 12 months among 10 patients.[21] The phase III GADOLIN study evaluated obinutuzumab in combination with bendamustine followed by maintenance obinutuzumab in the same disease setting (N = 413).[22] While the response rates by independent review were similar to those observed in the comparative arm of patients randomized to single-agent bendamustine (bendamustine-obinutuzumab ORR, 69% [CR, 11%] vs bendamustine alone ORR, 63% [CR, 12%]), the median PFS was significantly higher with the combination (not reached vs 14.9 months; P = .00011). Treatment with the combination of bendamustine and obinutuzumab was associated with a similar incidence of grade ≥ 3 adverse events compared with bendamustine monotherapy (68% vs 62%), which included neutropenia (33% vs 26.3%) and infusion-related reactions (9% vs 3.5%). While there was no difference in overall survival (OS) noted, the study did demonstrate the clinical benefit of obinutuzumab in rituximab-refractory disease. The role of the drug in this setting is becoming less clear, as more patients now receive bendamustine-rituximab as front-line therapy. In the phase Ib GAUDI study, bendamustine-obinutuzumab and obinutuzumab-CHOP produced similar response rates in patients with previously untreated follicular lymphoma, with ORRs of 93% (CR, 39%) and 95% (CR, 35%), respectively.[23] The incidences of grade 3/4 neutropenia and infection were similar to historical data on rituximab chemotherapy. These data prompted the front-line phase III GALLIUM study of chemotherapy (CHOP, CVP [cyclophosphamide, vincristine, and prednisone], or bendamustine) with obinutuzumab or rituximab followed by maintenance obinutuzumab or rituximab in advanced-stage indolent B-cell NHL (ClinicalTrials.gov identifier: NCT01332968). Newer monoclonal antibodies directed against CD20, such as ublituximab, and rituximab biosimilars are also in development.

Monoclonal antibodies to alternative targets

Monoclonal antibodies directed against other B-cell antigens have also been developed. Galiximab, a chimeric human-macaque anti-CD80 antibody, and epratuzumab, a humanized anti-CD22 antibody, were two of the first antibodies directed against these targets to be explored in follicular lymphoma. Both antibodies have shown activity as single agents and in combination with rituximab in follicular lymphoma. However, neither is being studied further due to the availability of newer, more promising therapies.[24-28] MEDI-551, an afucosylated humanized anti-CD19 antibody, induces cell death via ADCC and cytotoxic T-cell response. The lack of a fucose moiety on the Fc portion of the antibody is believed to enhance the activity of ADCC. Phase I studies of MEDI-551 in heavily pretreated follicular lymphoma have reported ORRs ranging from 31% to 82%.[29,30] The median PFS from the earlier study was nearly 10 months. MEDI-551 is currently being evaluated in aggressive lymphomas in combination with rituximab and salvage chemoimmunotherapy (ClinicalTrials.gov identifiers: NCT00983619 and NCT01453205). Also targeting CD19 is MOR208, a humanized monoclonal antibody that has been engineered to have a higher affinity to FcγRIIIa and FcγRIIa, resulting in stronger ADCC. In a phase II study of patients with relapsed and refractory B-cell NHL who had received a median of two prior therapies, the ORR was 26% among those with follicular lymphoma (n = 31).[31] The median duration of response (DOR) was 2.6 months; however, the longest DOR was 15.4 months. Upcoming trials with MOR208 include combination studies with lenalidomide in diffuse large B-cell lymphoma (DLBCL) and CLL (ClinicalTrials.gov identifiers: NCT02399085 and NCT02005289).

Radioimmunotherapy

One of the first attempts to improve upon the efficacy of the naked monoclonal antibody was radioimmunotherapy, which produced ORRs of 65% to 74% in patients with relapsed and refractory indolent B-cell lymphomas.[32,33] 90Y-ibritumomab tiuxetan, the first radioimmunotherapy to receive FDA approval, was approved in February 2002 for relapsed or refractory low-grade, follicular, or transformed B-cell NHL. In 2009, it was granted expanded approval as consolidation therapy in previously untreated follicular lymphoma patients with a partial or complete response to first-line chemotherapy. 131I-tositumomab was approved in June 2003 (along with tositumomab) for CD20-positive follicular NHL, with and without transformation, in relapsed rituximab-refractory patients with relapse following chemotherapy. The use of 131I-tositumomab and 90Y-ibritumomab tiuxetan has declined significantly over the past several years; the manufacture and sale of 131I-tositumomab (marketed in the United States and Canada as Bexxar) was stopped in February 2014. Radioimmunotherapy can be difficult; there are strict hematologic criteria (< 25% lymphomatous marrow involvement, platelet count > 100 × 109, leukocyte count > 1.5 × 109), and its administration requires a certified nuclear medicine physician. In addition, the patient must not have had prior radiation to > 25% of the bone marrow nor undergone stem cell transplantation.[34]

Antibody-drug conjugates (ADCs)

Recent efforts in augmenting antibody-based therapy include the use of ADCs. Once bound to its target antigen, the ADC is engulfed via endocytosis, trafficked to the lysosome for degradation, and ultimately released, whereupon it causes damage to tubulin and DNA. The calicheamicin-bound anti-CD22, inotuzumab ozogamicin, was one of the first to be studied in patients with follicular lymphoma who were refractory to CD20-targeted therapy, yielding an ORR of 66%.[35] The ORR increased to 87% when inotuzumab ozogamicin was combined with rituximab in patients with relapsed and refractory follicular lymphoma, prompting a trial in which it was compared with combination treatment with rituximab plus chemotherapy.[36] The trial was closed early due to poor accrual. Inotuzumab ozogamicin is currently being studied in combination with the mammalian target of rapamycin (mTOR) inhibitor temsirolimus in relapsed and refractory CD22-expressing NHL (ClinicalTrials.gov identifier: NCT01535989). Pinatuzumab vedotin and polatuzumab vedotin, which target CD22 and CD79b, respectively, are ADCs linked to the anti-tubulin molecule monomethyl auristatin E. While both agents have demonstrated activity in indolent NHL (with reported ORRs of 50% and 47%, respectively), polatuzumab vedotin is being taken further in development.[37,38] When polatuzumab vedotin was administered at a higher dose (2.4 mg/kg) with rituximab in patients with relapsed and refractory follicular lymphoma (n = 25), the ORR was 76% (CR, 44%) and median PFS was 15 months.[39] The cohort of 20 patients treated at the lower rituximab dose (1.8 mg/kg) had a similar response rate (ORR, 70%; CR, 40%), and median PFS and DOR were not reached. Peripheral neuropathy, a common toxicity with ADCs, occurred less frequently with the lower dose of polatuzumab vedotin and was ameliorated in some patients by dose delay and reduction. Ongoing studies with polatuzumab vedotin include phase I/II combinations with bendamustine-rituximab or obinutuzumab-bendamustine in relapsed and refractory follicular lymphoma (ClinicalTrials.gov identifier: NCT02257567) and R-CHOP in B-cell NHL patients who have received less than one prior therapy (ClinicalTrials.gov identifier: NCT01992653). Coltuximab ravtansine (formerly SAR3419) is an anti-CD19 ADC that has also been associated with neurologic complications, primarily dose-limiting ocular toxicity.[40] IMGN529, which targets the overexpressed CD37 protein, is another B-cell–directed ADC in development.[41]

Despite high rates of response to initial chemoimmunotherapy, patients with follicular lymphoma experience frequent relapses, and better treatment options are needed. Several novel biologic agents have been developed based on a greater understanding of the intrinsic factors driving the development of this heterogeneous disease. Such therapies target extracellular surface proteins and intracellular signaling pathways, as well as manipulate and engage the tumor microenvironment. Many of these agents have shown great promise in early-phase studies and are the focus of ongoing clinical investigations.

Small-Molecule Inhibitors – PI3K inhibitors

In contrast to the various antibody-based therapies under investigation for treatment of follicular lymphoma, several small molecules have been designed to inhibit key intracellular pathways of the malignant B cell. The majority of these agents are directed against kinases downstream of the B-cell receptor, and many have been combined with bendamustine-rituximab, given this combination’s efficacy and tolerability. Idelalisib, a potent PI3K-δ inhibitor, was the first PI3K inhibitor to be approved by the FDA for follicular lymphoma. It received an indication for patients who have received at least two prior systemic therapies, based on results of a phase II study in rituximab-refractory indolent NHL[42] As reported at the 2015 American Society of Clinical Oncology Annual Meeting, of the 72 patients in the study who had follicular lymphoma, 54% were considered high-risk by the Follicular Lymphoma International Prognostic Index.[43] The patients had received a median of four prior therapies, and 86% had disease that was refractory to the last regimen they received. The ORR was 56% and the median PFS was 11 months. The median PFS for the 10 patients who achieved a CR was 27 months. Notable grade 3/4 adverse events included neutropenia (27% of all patients), diarrhea/colitis (16%), elevations in hepatic transaminases (13%), and pneumonia (7%).
Idelalisib was subsequently administered with rituximab, bendamustine, and bendamustine-rituximab in a phase I study of patients with relapsed (n = 79) and refractory (n = 59) indolent NHL, the majority of whom had follicular lymphoma.[44] The ORRs were similar between the arms (75% to 88%); however, treatment with bendamustine-rituximab-idelalisib was associated with the highest CR (43%) and longest median PFS (37.1 months). A phase III trial of bendamustine-rituximab with or without idelalisib in relapsed and refractory indolent B-cell NHL is ongoing (ClinicalTrials.gov identifier: NCT01732926). In phase I investigations, combined treatment with idelalisib and lenalidomide plus the second-generation SYK inhibitor entospletinib has demonstrated considerable toxicity, including hepatic transaminitis, sepsis, and refractory pneumonitis.[45,46] Second-generation PI3K inhibitors, including duvelisib (IPI-145), TGR-1202, and INCB040093, are in development. Duvelisib, a dual inhibitor of the delta and gamma isoforms of PI3K, has demonstrated an ORR of 69% (CR, 38%) in a heavily pretreated follicular lymphoma cohort (n = 13).[47] Based on these encouraging data, duvelisib is being administered with rituximab or obinutuzumab in patients with previously untreated follicular lymphoma (ClinicalTrials.gov identifier: NCT02391545) and with bendamustine and/or rituximab in those with relapsed B-cell malignancies (ClinicalTrials.gov identifier: NCT01871675).

Bruton tyrosine kinase (BTK) inhibitors

Ibrutinib, a selective and irreversible inhibitor of BTK, may also have some impact on the tumor microenvironment via cytokine and chemokine inhibition.[48] Approved in CLL, mantle cell lymphoma, and Waldenström macroglobulinemia, it has demonstrated activity in a number of B-cell malignancies.[49-53] In a phase II study of relapsed and refractory follicular lymphoma, ibrutinib yielded an ORR of 30% (with one CR) and a median PFS of 9.9 months. The 40 enrolled patients had received a median of three prior therapies, and 36% were considered refractory to treatment. Common adverse events included mild diarrhea, rash, and fatigue; rare events included atrial fibrillation and bleeding.[54] Like idelalisib, ibrutinib has been combined with bendamustine-rituximab in the treatment of B-cell NHL.[55] This triplet produced an ORR of 90% (CR, 50%) in a cohort of 10 patients with previously treated follicular lymphoma. At the time these results were reported, the median PFS had not been reached. Notable grade 3/4 adverse events included neutropenia (33%), rash (25%), and thrombocytopenia (19%). Results from SELENE, a randomized phase III trial of ibrutinib with bendamustine-rituximab or R-CHOP in previously treated follicular lymphoma and marginal zone lymphoma, will provide more insight into the role of ibrutinib in the management of indolent NHL (ClinicalTrials.gov identifier: NCT01974440). Phase I trials of combinations with targeted agents include the Alliance for Clinical Trials in Oncology study of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma[56] and the pharmaceutical-sponsored trial of combination therapy with ublituximab, TGR-1202, and ibrutinib in relapsed and refractory B-cell malignancies.[57] Second-generation BTK inhibitors, including ACP-196 and ONO-4059, are also in development.

B-cell lymphoma–2 (BCL-2) inhibitors

The chromosomal translocation t(14;18) allows for dysregulation of the BCL-2 oncogene and overexpression of the anti-apoptotic BCL-2 family of proteins, contributing to development of follicular lymphoma. Venetoclax, formerly known as ABT-199, is a second-generation selective BCL-2 inhibitor in the early stages of clinical investigation. When this agent was administered at a dose greater than 600 mg daily to six patients with relapsed and refractory follicular lymphoma, three patients achieved a response.[58] Common toxicities reported included mild nausea (34%) and diarrhea (25%), and grade 3/4 myelosuppression occurred in less than 15% of patients. Two patients (one with DLBCL and one with mantle cell lymphoma) in the entire NHL cohort (of 44 patients then enrolled in the study) developed laboratory evidence of grade 3 tumor lysis syndrome. When venetoclax was combined with bendamustine-rituximab in 21 patients with relapsed and refractory follicular lymphoma, the ORR was 71% (CR, 29%).[59] While a maximum tolerated dose was not reached, dose-limiting toxicities included thrombocytopenia, neutropenia, and Stevens-Johnson syndrome. Venetoclax is being evaluated in relapsed and refractory follicular lymphoma, in a three-arm phase II study of bendamustine-rituximab vs rituximab-venetoclax vs bendamustine-rituximab-venetoclax (ClinicalTrials.gov identifier: NCT02187861). It will be studied with ibrutinib in a phase I/II trial of relapsed follicular and marginal zone lymphoma (Ujjani C, principal investigator). Small-molecule inhibitors aimed at less well known targets are also under investigation, including selinexor (a selective inhibitor of nuclear export), MK-2206 (an AKT inhibitor), alisertib (an Aurora-A kinase inhibitor), and cerdulatinib (a dual SYK/Janus tyrosine kinase [JAK] inhibitor).

TO PUT THAT INTO CONTEXT

Loretta J. Nastoupil, MD
Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Houston, Texas

What Are the Challenges of Treating Follicular Lymphoma?

Follicular lymphoma, the most common indolent lymphoma, is characterized by high rates of initial response to chemoimmunotherapy, but it is not curable with standard therapy. The clinical course of the disease is highly variable and somewhat unpredictable. As a result, the optimal management of follicular lymphoma, including the most effective sequencing of therapy, is undefined. Identifying the subsets of patients at risk for early failure and those with indolent disease that remains quiescent would assist clinicians in tailoring therapy for individual patients. Given the heterogeneity of treatment options and possible clinical outcomes, improvement in risk stratification and personalization in follicular lymphoma is needed, particularly given the expanding treatment options outlined by Dr. Ujjani.

What Can We Expect in the Future?

Historically, prognostication for patients with follicular lymphoma has relied primarily on clinical characteristics. The Follicular Lymphoma International Prognostic Index (FLIPI) can distinguish patients with low or intermediate risk from those at high risk, but it is not routinely used to guide risk-adapted therapy. More recently, the development of m7-FLIPI, a multivariable risk model incorporating the mutation status of seven genes with established clinical relevance in follicular lymphoma, improved the ability to predict early treatment failure in patients receiving front-line chemoimmunotherapy. Identifying the follicular lymphoma patients at highest risk for early treatment failure with standard therapy allows for their prioritization to a clinical trial assessing some of the novel therapies outlined by Dr. Ujjani.

Given the number of therapeutic agents under investigation in follicular lymphoma, and the vast combinatorial possibilities, consideration of toxicity is as imperative as the need to conduct correlational studies to unravel the complexity of this disease.

Tumor Microenvironment
Immunomodulatory agents

As stated previously, the tumor microenvironment plays a critical role in the pathogenesis of follicular lymphoma. Approaches to promoting a functional immune system have allowed for effective treatment of the disease. The second-generation immunomodulatory agent lenalidomide has been the most extensively studied of these therapies. Its mechanisms of action include activation of natural killer cells and T cells, stimulation of apoptosis, and inhibition of tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF).[60] In follicular lymphoma cell lines, lenalidomide has been shown to restore immunologic synapses between malignant lymphocytes and T cells and augment rituximab-mediated ADCC.[61] Lenalidomide has demonstrated modest activity as a single agent in relapsed or refractory follicular lymphoma (with ORRs ranging from 27% to 49%); however, when lenalidomide was added to rituximab the ORR improved to 76% and the median event-free survival time was 2 years.[62,63] The doublet (dubbed “R2,” for Revlimid [lenalidomide] plus rituximab) was evaluated by the Alliance study as a front-line regimen, producing an ORR of 93% (CR, 72%) and 2-year PFS of 89% (n = 65).[64] Minimal toxicity was noted with the regimen; common grade 3/4 adverse events included neutropenia (in 19% of patients), rash (8%), and infection (8%). In a similar study from the University of Texas MD Anderson Cancer Center, 35 of the 50 patients with follicular lymphoma achieved a CR (70%) and 5 had an unconfirmed CR.[65] The Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group reported an ORR of 78% (CR, 61%) with the R2 combination (n = 77).[66] The impressive activity noted in the Alliance and MD Anderson studies prompted the pharmaceutical-sponsored phase III RELEVANCE trial of R2 vs rituximab with chemotherapy (CVP, CHOP, or bendamustine) in previously untreated advanced-stage follicular lymphoma (ClinicalTrials.gov identifier: NCT01650701). R2 has been studied in combination with other regimens such as CHOP, producing an ORR of 94% (CR/unconfirmed CR, 74%) in patients with previously untreated follicular lymphoma.[67] These data are relatively comparable to previously reported results with R2 and call into question the need for CHOP. The Alliance has conducted subsequent studies of R2 with targeted agents including ibrutinib and idelalisib. Results with ibrutinib are pending; however, the trial of idelalisib was closed owing to considerable toxicity.[45,56] Lenalidomide has also been combined with obinutuzumab in the treatment of relapsed and refractory disease, yielding an ORR of 68% (CR, 35%) among the 20 patients enrolled in the phase I portion of a phase I/II study.[68]

Immune checkpoint modulators

In patients with follicular lymphoma, the overexpression of PD-1 in the intratumoral T cells results in an impairment in antitumor immune surveillance. Inhibition of PD-1 or its ligands, PD-L1 and PD-L2, has shown promise in the treatment of follicular lymphoma. Pidilizumab, a humanized PD-1 monoclonal antibody, was the first PD-1 inhibitor to be explored. Although minimally active as a single agent, when pidilizumab was administered in conjunction with rituximab in the setting of relapsed follicular lymphoma, the ORR was 66% and median PFS was 18.8 months (n = 29).[69,70] The majority of the responses were complete (52%), and the median PFS had not been reached for those who achieved a response. Nivolumab, a fully human monoclonal antibody approved for the treatment of melanoma and squamous non–small-cell lung cancer, has also demonstrated activity in relapsed and refractory follicular lymphoma. A phase I evaluation has reported an ORR of 40% (CR, 10%) in 10 patients.[71] Nivolumab is currently being studied in combination with ibrutinib in patients with relapsed B-cell malignancies (ClinicalTrials.gov identifier: NCT02329847). Pembrolizumab and MEDI-0680 are humanized PD-1 antibodies also under clinical investigation in CLL and other low-grade B-cell NHLs, as well as in relapsed and refractory aggressive B-cell lymphomas (ClinicalTrials.gov identifiers: NCT02332980 and NCT02271945, respectively). MEDI4736, a human anti–PD-L1 antibody, is also being studied with ibrutinib in patients with relapsed lymphoma (ClinicalTrials.gov identifier: NCT02401048). Similar to PD-1, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative regulator of T-cell function. Inhibition of CTLA-4 with ipilimumab, also approved in melanoma, has demonstrated some activity in lymphoid malignancies, including in one patient with follicular lymphoma.[72]

Bispecific T-cell engager (BiTE)

The BiTE is a unique form of immunotherapy that stimulates T-cell function via binding simultaneously to CD3 on the surface of the T cell and a specific marker on the malignant B cell, resulting in caspase-mediated apoptosis. Blinatumomab, a CD19-specific BiTE approved for treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (ALL), has demonstrated activity in other CD19-positive lymphoid diseases.[73] It produced an ORR of 100% in a phase I study of 13 patients with relapsed indolent NHL, the majority of whom had a follicular or mantle cell histology.[74] Four patients achieved a CR, and eight remained in remission at 13 months. A single cycle of blinatumomab requires a 4-week continuous IV infusion and is associated with significant, yet reversible, neurologic toxicity. The current focus of clinical investigations with this agent is ALL, and its role in follicular lymphoma is unclear.

Chimeric antigen receptor (CAR)-modified T cells

CAR-modified T cells are one of the newest, most intriguing, forms of immunotherapy. These autologous T cells have been genetically transduced using lentiviral vectors to express tumor cell–specific antigen receptors. Having demonstrated activity in CLL and ALL, CAR-modified T cells are now being explored in CD19-positive NHL. A phase II study at the University of Pennsylvania demonstrated an ORR of 100% among seven patients with relapsed and refractory follicular lymphoma who lacked curative treatment options.[75] Six patients achieved a CR by 6 months, and responses appeared to be durable. In all seven patients there was evidence of severe cytokine release syndrome (cytokine storm); in two of the patients this was a grade 3/4 toxicity. One patient developed grade 5 encephalopathy 2 months after completing therapy. Although quite promising, further investigation is necessary to fully understand this new method.

Conclusion
The treatment of follicular lymphoma has changed dramatically over the past several years. The availability of newer, novel forms of therapy has enabled the field to continue to evolve. In addition to having tumor-specific activity, these newer agents provide the possibility of a more favorable toxicity profile than conventional chemotherapy. Although chemoimmunotherapy has been the traditional front-line induction for patients with advanced-stage disease, this concept is being challenged by the remarkable efficacy of the R2 regimen (with ORR > 90%; CR, 61% to 72%).[64,66] If the phase III RELEVANCE trial demonstrates results with R2 that are even equivalent to those achieved with standard regimens such as R-CHOP or bendamustine-rituximab, a major paradigm shift will occur; R2 would then be the first chemotherapy-free option for the initial treatment of follicular lymphoma. Given that the attainment of a CR has been associated with a survival benefit in this setting, there is still room for improvement.[76] Although approved as a single agent, idelalisib is being studied in combination with rituximab in previously untreated and relapsed patients (ClinicalTrials.gov identifiers: NCT02258529 and NCT01732913). Ongoing clinical investigations, such as the Alliance phase I trial of R2 plus ibrutinib in previously untreated patients, are exploring the benefit of multitargeted agents in this population. Studies such as the phase II trial of bendamustine-rituximab vs rituximab-venetoclax vs bendamustine-rituximab-venetoclax are exploring the utility of other targeted agents in comparison to standard chemoimmunotherapy.

While the concept of multitargeted therapy is quite appealing, these regimens must be explored with caution. Early-phase investigations of idelalisib with R2 and entospletinib produced significant adverse events, requiring study closures.[45,46] In addition to understanding how to combine treatment with these agents safely and efficaciously, research efforts must incorporate sound correlative science. Through whole-exome sequencing, Woyach et al have already discovered mutations associated with resistance to ibrutinib in CLL.[77] The identification of other predictive biomarkers is imperative to tailor therapy effectively and to develop superior regimens for individual patients. Furthermore, this information may enable us to provide appropriate treatment options that are also financially prudent. Given the lengthy follow-up period required to achieve the traditional objectives of clinical trials, it is important to explore earlier, yet meaningful, surrogate endpoints. Residual positron emission tomography activity on post-induction imaging, the presence of minimal residual disease, and relapse within 2 years of chemoimmunotherapy have been associated with an inferior PFS and OS outcome; in contrast, the presence of a CR at 30 months has been correlated with a significantly reduced risk of progression in patients with follicular lymphoma.[78-81] By incorporating novel therapies into innovative clinical investigations, we may achieve significantly better outcomes and improve the outlook for patients with this incurable disease.

Financial Disclosure: Dr. Ujjani has served on advisory boards for Genentech, Inc., and Pharmacyclics, Inc.

 

 

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