Christopher R. Flowers, MD

Follicular lymphoma (FL) and other forms of indolent non-Hodgkin lymphoma (iNHL) are commonly considered incurable diseases with continual risk of relapse over time, shorter durations of response with each subsequent line of therapy, and a risk of transformation to a more aggressive B-cell lymphoma. Although these lymphomas are characterized as indolent, one of the most common causes of death for these patients is lymphoma.

 On the other hand, a significant proportion of patients worldwide live disease-free for a decade or longer following first-line therapy, with various approaches suggesting that there may be pathways to develop approaches for a cure for at least a subset of patients.

 In the “Indolent B-Cell Lymphoma” session during the Society of Hematologic Oncology 2021 Annual Meeting, 4 presentations were explored: “Molecular Pathogenesis of Follicular Lymphoma and Its Relevance to Clinical Practice,” “Sequencing Therapy in Follicular Lymphoma,” “Novel Therapies in Indolent Lymphoma,” and “CAR T-Cell Therapy in Indolent Lymphoma” in lectures by world-class experts Jessica Okosun, MA, MB BChir, MRCP, FRCPath, PhD, Peter Martin, MD, Loretta Nastoupil, MD, and Caron Jacobson, MD, MMSc.

Next-generation sequencing studies, led by Michael R. Green, PhD, Dr Okosun, and others, have described the panoply of genomic events involved in FL and have aided in identifying candidate genetic drivers

 This work clarified the diverse genomic landscape and the temporal clonal dynamics of FL. Common genomic events that occur with t(14;18) include high frequencies of mutations affecting epigenetic regulation, disruptions in pathways such as those involved in immune recognition (eg, 

).9,10 Next-generation sequencing also has been used to examine factors associated with progression of FL, transformation of iNHL to more aggressive lymphomas, and spatial heterogeneity in FL. Recent studies have explored the subclonal diversity and spatial heterogeneity observed among patients with FL that have potential clinical implications for the development of prognostic and predictive biomarkers and targeted treatment strategies. For instance, exome sequencing of FL tumors and paired germline have identified nonsynonymous somatic variants corresponding to missense (81%), indels (10%), nonsense (7%), and splice site (2%) changes.

 This work revealed spatially discordant mutations in genes such as 

One attractive treatment paradigm emerging from this work involves specifically targeting highly recurrent and truncal gene mutations that have roles in FL pathogenesis. Other studies did not identify a single compelling genetic event responsible for transformation, but instead suggest that the acquisition of certain genetic alterations may result in aggressive transformation.

 Exploration of the FL genomics in this session can clarify stratified treatment approaches targeting specific early genetic lesions identified in FL and may eventually provide strategies to eradicate these cell populations and provide pathways to cure FL.

In the past decade, many new agents have been introduced for the management of FL, and therapeutic strategies have evolved over time. Recently, my co-chair in this session, Nathan Fowler, MD, and I reviewed data from trials addressing the safety and efficacy of lenalidomide alone and in combination with rituximab as a first-line therapy and as a treatment of patients with relapsed/refractory FL.

However, since that review other agents have received FDA approval for patients with relapsed FL. There is considerable variation in response rates for recently approved therapies ranging from objective response rates of 40% to 60% for PI3K inhibitors, 35% to 65% for EZH2 inhibitors, and greater than 70% for autologous stem cell transplantation, and CD19-directed chimeric antigen receptor (CAR) T-cell therapy.

 Recently approved therapies in relapsed FL have commonly been based on response rate and duration of response (DOR) demonstrated in phase 2 studies. However, despite numerous trials performed in the field, there is no single standard of care for patients with iNHL who are undergoing second-line treatment or beyond.

As a result of the patterns of relapse and transformation associated with iNHL, the clinical treatment of patients with FL and other iNHLs often requires multiple lines of therapy using various regimens with different mechanisms of action.

 The clinical benefits and adverse effects associated with the treatments available at relapse vary and are influenced by patient and disease characteristics at the time of progression, the duration of the interval from last treatment, and the toxicity and responses associated with the treatments previously administered. This results in a marked heterogeneity of clinical situations encountered during the treatment of these patients. Some patients with iNHL will remain well treated using available treatments, whereas others will develop disease refractory to conventional approaches and become candidates for novel treatments and clinical trials. Additional real-world data regarding patient characteristics at relapse, patterns of care, expectations of response rates and duration, and survival outcomes are lacking in the setting of relapsed and refractory iNHL. To help inform treatment decisions by health care providers treating patients with iNHL in this complex and evolving treatment landscape, Dr Martin will describe approaches for sequencing therapies. To optimally individualize treatment strategies for patients with previously untreated and relapsed iNHL, the risks and benefits of the available options should be well known. This lecture will enable providers to effectively discuss the goals of therapy with the patient at each intervention, which is also critical in providing an optimal sequence of therapy.

Although many patients with FL experience long or possibly near-normal life expectancies, there remains persistent variability in patient outcomes.

 Patients who relapse within 2 years of first-line chemoimmunotherapy or with histologic transformation are at risk for early mortality and are high-priority candidates for novel treatment strategies evaluated in clinical trials.

Prior studies have demonstrated diminishing DOR by line of therapy.

However, variability of iNHL disease biology, treatment options, and treatment patterns complicate outcome assessments based on line of therapy alone. Several novel and targeted therapies are being developed and evaluated in patients with relapsed iNHL, including cereblon inhibitors, anti–CD20-CD3 bispecific antibodies, and additional anti-CD19 CAR T-cell therapies. Dr Nastoupil will provide key insights on the novel therapies available for patients in clinical trials and those that are establishing pathways toward applications in clinical settings.

CAR therapy targeting CD19 is one promising treatment for patients with relapsed or refractory FL and CD19+ iNHLs. Patients who are candidates for CAR T-cell therapy often have symptomatic disease that could be fatal if left untreated. Dr Jacobson will discuss strategies for bridging therapy, which may include chemotherapy, targeted therapy, or radiation therapy; approved and experimental CAR T-cell approaches for FL and iNHLs; and describe traditional and novel adverse events and outcomes from clinical trials involving CAR T-cell therapy.

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8. Green MR, Kihira S, Liu CL, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. 

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11. Okosun J, Montoto S, Fitzgibbon J. The routes for transformation of follicular lymphoma. 

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12. Flowers CR, Leonard JP, Fowler NH. Lenalidomide in follicular lymphoma. 

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13. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. 

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14. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. 

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15. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. 

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16. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of zuma-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (r/r) indolent non-Hodgkin lymphoma (iNHL). 

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19. Flowers CR, Leonard JP, Nastoupil LJ. Novel immunotherapy approaches to follicular lymphoma. 

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20. Leonard JP, Nastoupil LJ, Flowers CR. Where to start? Upfront therapy for follicular lymphoma in 2018. 

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21. Nastoupil LJ, Flowers CR, Leonard JP. Sequencing of therapies in relapsed follicular lymphoma. 

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22. Salles G. How do I sequence therapy for follicular lymphoma? 

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23. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. 

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24. Casulo C, Friedberg JW, Ahn KW, et al. Autologous transplantation in follicular lymphoma with early therapy failure: a National LymphoCare Study and Center for International Blood and Marrow Transplant Research analysis. 

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25. Casulo C, Nastoupil L, Fowler NH, Friedberg JW, Flowers CR. Unmet needs in the first-line treatment of follicular lymphoma. 

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Articles

A significant proportion of patients worldwide live disease-free for a decade or longer following first-line therapy, with various approaches suggesting that there may be pathways to develop approaches for a cure for at least a subset of patients

Pursuing Optimal Therapy Remains a Challenge in Indolent B-Cell Lymphoma

Christopher R. Flowers, MD, department chair of the Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the current therapies used for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and goes into specifics of the L-MIND trial (NCT02399085) after the long-term follow-up.

There are multiple therapies and therapy combinations approved in this setting, including chimeric antigen receptor (CAR) T-cell therapy. The 2021 American Society of Clinical Oncology (ASCO) Annual Meeting provided some updated for trials in this space, including the multicenter, open-label, single-arm, phase 2 study L-MIND trial.

What we have, however, seen is a dramatic change in the numbers of therapies that are available in the relapse setting. That's with the advent of polatuzumab [Polivy] combined with bendamustine and rituximab [Rituxan], tafasitamab [Monjuvi] combined with lenalidomide [Revlimid], and now loncastuximab tesirine [Zynlonta] approved in that third or later line space of therapy, and the advent of 3 different CAR T-cell therapies that are now approved in the relapse setting for DLBCL. Then selinexor [Xpovio] that's also approved in that space. So really a whole host of options. At this year's ASCO meeting, we saw an update on some of those trials, and particularly the one looking at the combination of tafasitamab and lenalidomide, or the L-MIND trial.

What were the design and efficacy of the L-MIND trial?

 When we look at the L-MIND trial, it's a trial that was published with updated results in 

 in 2020 describing a patient population of about 81 patients. When you look at the characteristics of the population, the median age at the time of enrollment was about 72 years, which is relatively similar to what we would see for a general population of patients with DLBCL; 11% of those patients had a prior stem cell transplantation. This is generally an older patient population who did not have transplant as part of their course of care. The majority of patients had a median of 2 prior lines of therapy, so still relatively early in their treatment cycle. When you look at response rates, and particularly when you look at response rates by numbers or prior lines of therapy, what was presented in the updated results at ASCO showed for those patients who had 1 prior line of therapy, that the complete response rate was 48% versus those who had 2 or more prior lines of therapy, and the trial was divided about half and half between those 2 different groups. Those who had 2 or more prior lines of therapy had a complete response rate of 33%. The duration of response appeared to be quite durable for both groups being more than 44 months in both groups of responders.

Videos

Christopher R. Flowers, MD, discusses the current therapies used for patients with relapsed/refractory diffuse large B-cell lymphoma and goes into specifics of the L-MIND trial after the long-term follow-up.

Reviewing Current Therapies in Relapsed DLBCL and the L-MIND Trial

 This patient’s situation addressed one of the key unmet needs with follicular lymphoma, and that’s patients who experience early relapse. I’ve been engaged in a US intergroup trial that evaluates those 3 arms with therapies for those patients who experience early relapse. I think that’s a very important trial to accrue patients to, to help answer this question.

The other unmet needs that are being addressed are those patients with aggressive forms of relapse or transformation.

CAR [chimeric antigen receptor] T cells are another promising therapy that is available for patients with follicular lymphoma, and I think new trials need to be explored to ascertain where those might be best utilized in the relapsed and refractory setting, particularly for patients who experience more aggressive disease.

There are now many new, novel targeted immunotherapies for patients with follicular lymphoma, and we’re moving into an era where chemotherapy-free regimens may be possible for patients in the first line of therapy and with each subsequent line of relapse.

It’s a very promising time for new therapies and new clinical trials for patients with follicular lymphoma.

Case:A 77-Year-Old Man With Follicular Lymphoma

A 77-year-old man complains of a 4-month history of occasional fevers, decreased appetite, and an unintentional 7-lbs. weight loss

PE: palpable left axillary lymph nodes ~ 4 cm; spleen palpable 4.5 cm below costal margin



Labs: ANC 1.5 x 109/L, WBC 10.6 x 109/L, 42% lymphocytes, Hb 10.1 g/dL, plt 100 x 109/L, LDH 325 U/L, B2M 3.3 µg/mL; HBV negative

Bone marrow biopsy showed lymphoid aggregates, 35% involvement

PET/CT showed enlargement of left axillary, mediastinal and bilateral para-aortic lymphadenopathy (4.2 cm, 5.3 cm, 3.6 cm and 3.5 cm respectively)

He was treated with R-CHOP for 6 cycles; continued rituximab maintenance 375 mg/m3; achieved partial response

6 months later he complained of increasing frequency of fevers

Repeat PET/CT revealed progression of disease

He was started on bendamustine + obinutuzumab for 6 cycles and continued maintenance obinutuzumab

Repeat lymph node biopsy grade 2 follicular lymphoma

8 months later he complained of increased weight loss

He was started on idelalisib 150 mg PO BID

Follicular Lymphoma Management: Future Directions

 The pivotal trial that led to the approval of idelalisib was led by a good friend and colleague, Ajay Gopal, MD, and published in 

 in 2014. That was a multi-institutional trial of the single-agent PI3-kinase inhibitor idelalisib, given as a single arm in that trial.

In that trial, the drug was administered to patients with relapsed/refractory follicular lymphoma when those patients had relapsed after both rituximab and, typically, cyclophosphamide. Those patients moved on to receive this PI3-kinase inhibitor in that setting.

In this relapsed/refractory population, we saw an overall response rate for patients above 40%, with a duration of response—it was quite meaningful for this population—of more than a year for the majority of patients.

When we think about the adverse events associated with idelalisib, those tend to be associated both with the acute administration of the drug and related to inflammatory toxicities, or activation of T cells, in particular.

Some of those acute events can be in the form of diarrhea, which is typically acute while the drug is being administered. That’s one that typically happens relatively shortly after the administration of the drug and typically goes away if you stop the drug. And then if you restart the drug, it does not recur.

Along those same lines, patients can sometimes experience nausea or fatigue associated with the administration of the drug. The later kinds of toxicities we also worry about are associated with inflammatory toxicities—the so-called itises associated with idelalisib or the other PI3-kinase inhibitors. There we can see transaminitis, or elevation of the liver function tests. Those also typically go away if you stop the drug. And if you restart at a lower dose, those often do not recur.

There is a second kind of diarrhea that is inflammatory that typically occurs later. That’s a kind of diarrhea for which if you stop the drug and restart therapy, the diarrhea will recur or won’t go away, and that often requires the use of steroids and may require discontinuation of the drug, if the diarrhea continues. Likewise, pneumonitis is also associated with idelalisib.

Idelalisib for Relapsed/Refractory FL

 The patient in this particular situation was someone who had a high FLIPI [Follicular Lymphoma International Prognostic Index] score and a relatively poor expected overall survival from his diagnosis, based on his advanced age and how advanced his disease was. For many patients with follicular lymphoma who fall into the lower FLIPI risk category or have a very good response to their initial line of therapy, their expected overall survival is not that much different from age-matched controls.

While follicular lymphoma is expected to be a disease that is not curable with standard therapy, many patients will have subsequent relapses and be treated and then retreated and retreated again. It is relatively common to now see patients who were treated in the third-line or fourth-line or even later lines of therapy.

When we think about the options available, there are now 3 PI3-kinase inhibitors that are approved in that setting. Idelalisib is one of those. Duvelisib is a second one of those that is approved in that setting. Copanlisib is an IV [intravenous] formulation of a PI3-kinase inhibitor that is also available.

When we think about relapsed and refractory follicular lymphoma, the efficacy of those drugs appears to be more similar than different. The response rates, overall, are in the 40% to 50% range for the majority of those agents, and patients have meaningful progression-free survival. It can be a year or more for the majority of those agents. The distinguishing features stand in terms of the ways the drugs are given. Copanlisib, as mentioned, is an agent that is given via an IV formulation.

Some physicians and patients may consider the IV formulation an advantage in that patients are getting therapy. You know they’re getting therapy when they come in to get their IV medication. For other patients and physicians, they may consider that a disadvantage when they could, instead, be taking a therapy that is administered as an oral agent at home and not need to come back to the physician’s office to get care.

The other thing that we see as a difference between those PI3-kinase inhibitors is the forms, or isoforms of PI3-kinase. Idelalisib is an inhibitor of the PI3-kinase delta. Copanlisib is a pan inhibitor of PI3-kinase, so it affects both the alpha and beta PI3-kinase. Those are ones that have other adverse effects associated with them, so patients need to be monitored closely for hypertension while the drug is being infused and need to be monitored for hyperglycemia, which can cause additional difficulties if the patient has predisposition to diabetes or hyperglycemia for other reasons. The other form of PI3-kinase inhibitor, duvelisib, is more similar in nature to the PI3-kinase delta inhibitor, idelalisib.

PI3K Inhibitors for Relapsed/Refractory FL

 For patients who relapse early after one of those chemoimmunotherapy regimens—bendamustine/rituximab or R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] being the most commonly used ones in the United States—those are patients who have very poor expected overall survival and progression-free survival.

In a landmark paper that was led by Carla Casulo, MD, from the National LymphoCare Study, we saw that patients who received R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] as their frontline regimen and then relapsed within 2 years of their primary therapy had a very poor expected overall survival of approximately 50% or less at 5 years. For those particular patients, we need to think about newer approaches.

There is a chemoimmunotherapy compared with targeted therapy approach being explored in a randomized trial for patients with an early relapse. That is a US intergroup trial looking at the combination of bendamustine/obinutuzumab for those who had R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] as their frontline regimen, or obinutuzumab/CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] for those who had bendamustine as their first-line chemoimmunotherapy regimen. That is 1 arm of the trial. Lenalidomide/obinutuzumab is the second arm of the trial, and a PI3-kinase inhibitor, umbralisib, and obinutuzumab is a third arm in the trial. That really should be the preferred approach for this poor-risk patient population.

For those patients who are unable or unwilling to go on a clinical trial, the kinds of regimens that we might think about in the relapsed setting as approved regimens are bendamustine/obinutuzumab, which this patient got in this particular situation; or lenalidomide and rituximab, which is now approved based on the AUGMENT trial in the relapsed and refractory setting; or other forms of chemoimmunotherapy.

For those patients who are young enough and healthy enough, autologous stem cell transplantation should be considered after that. Those typically would be patients under the age of 70 who are fit and well enough to undergo an autologous stem cell transplantation.

There are also more clinical trials exploring CAR [chimeric antigen receptor] T cells in this setting for patients who have an early relapse.

While this patient experienced an early relapse of follicular lymphoma, which again, happens in about 20% of individuals, the majority of patients will experience a later relapse, something longer than 2 years after initial therapy. For those patients, there are numerous approaches available.

Occasionally, single-agent rituximab can be used in that setting to control disease and help prevent a subsequent relapse. In addition, lenalidomide/rituximab is now approved in that setting. Bendamustine/obinutuzumab is another option, and any other first-line chemoimmunotherapy regimens that weren’t used in the first-line setting are also potential options for use in the second line for a relapse.

For patients who experience a second relapse after that first, early relapse, there are a number of other agents, including those that I just mentioned, that would be options. And additionally, the PI3-kinase inhibitors, by themselves, are approved in this setting.