John M. Burke, MD

 I think, because of the complexity of this disease and that it is not super common, that my practical advice for a community oncologist managing this disease would be to remember, when you have patients who experience a relapse, to have early discussion with your stem cell transplanters and your CAR [chimeric antigen receptor] T-cell therapy providers. Getting patients referred early for those modalities is important because this disease can progress quickly. There are logistical barriers to overcome to administer to patientsCAR T-cell therapy. The earlier you can get that process going, the more likely it is that your patients will be successful at receiving those potentially lifesaving therapies.

I think it is important for all of us to familiarize ourselves with these new drugs, particularly the polatuzumab vedotin-BR-tafa-len [bendamustine, rituximab, tafasitamab and lenalidomide] combination and Selinexor, so that we have the ability to prescribe them safely and effectively to our patients who need them. I encourage folks to move quickly because it is possible that, by treating patients quickly and soon in their relapse, we can sequence these drugs and these combinations one after the other so that we have the potential to turn DLBCL [diffuse large B-cell lymphoma] into a chronic disease rather than a rapidly progressive, fatal one, as it has been for so long. Making sure that our patients have the opportunity to receive all of these agents in a timely fashion is going to be important for extending their lifespans and controlling this disease for as long as possible.

Case: A 76-Year-Old Man with R/R DLBCL

A 76-year-old man presented with fatigue, loss of appetite

PMH: atrial fibrillation, hypertension, medically controlled

PE: palpable 5 cm right inguinal mass; bilateral axillary lymphadenopathy; splenomegaly

Excisional biopsy of the lymph node confirmed DLBCL, GCB subtype

FISH panel: t(14;18) with a BCL2 rearrangement

Whole body PET/CT scan showed diffuse lymphadenopathy , splenomegaly

First post-treatment PET/CT scan was unremarkable; CR

1 year later he presents with recurrent axillary lymphadenopathy

Repeat biopsy confirms relapse of DLBCL, GCB subtype

He was ineligible for high-dose chemotherapy and ASCT

Videos

John Burke, MD, provides clinical pearls in the recognition in treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

Clinical Pearls for Managing R/R DLBCL

 There are a number of additional novel agents available now for patients with relapsed DLBCL [Diffuse large B-cell lymphoma]. Of course, there are three CAR [chimeric antigen receptor] T-cell products on the market. These include axi-cel [axicabtagene ciloleucel], tisagenlecleucel, and liso-cel [Lisocabtagene maraleucel] which was just recently approved. As a rule, these have a high level of activity with overall response rates ranging between 50% and 80%, and complete remission rates ranging in the ballpark of 30% to 60%. Most of the products would have a 50% rate and with durable CRs [complete responses] being between 30% and 50%. These are highly effective treatments. Of course, they require quite a bit of logistics. They require referral to centers capable of delivering these treatments.

Many centers will hospitalize patients for the treatment due to the potential toxicities. The toxicity profiles of CAR T-cell therapy include cytokine release syndrome and neurological events. Another important agent is polatuzumab vedotin, given in combination with bendamustine and rituximab [pola-BR]. This was approved based on a randomized phase 2 trial demonstrating significant improvement in response rate, and even overall survival in patients treated with pola-BR in comparison with BR [bendamustine and rituximab] alone. One of the potential toxicities of polatuzumab vedotin to keep in mind is neurological or peripheral neuropathy and cytopenias, but it is still a very important drug now in patients with relapsed large cell lymphoma.

Finally, we also saw another new approval for Selinexor. It was FDA approved early last year. This was based on a study called the SADAL study, which enrolled patients who had received between 2 and 5 prior lines of therapy. The dosing of Selinexor for patients with large cell lymphoma is different from myeloma; patients with with large cell lymphoma are given 60 mg instead of 80 mg on days 1 and 3 of each week. A number of patients did require dose reductions due to toxicities.

The efficacy of Selinexor as a single agent is demonstrated in the overall response rate of 28% and complete response rate of 12%. The median of progression-free survival duration was only 2.6 months, but there were some patients in the trial with very durable remissions. Toxicities of Selinexor include cytopenias, hyponatremia, and then GI [gastrointestinal] toxicities such as anorexia and nausea. Selinexor does require a fairly aggressive antiemetic therapy as prevention for drug-induced nausea and vomiting. Those are the primary new agents available in patients with relapsed DLBCL.

John Burke, MD, reflects on current novel therapies used in the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

Novel Therapies for R/R DLBCL

 What data do we have to support the use of tafasitamab and lenalidomide, and why did that combination get approved? The trial that supported and was pivotal for that combination was called the L-MIND trial. This was published by Dr Salles [Gilles Salles, MD,] and others in 

 in 2020. Tafasitamab's mechanism of action is that it is an anti-CD19 [B-lymphocyte antigen] monoclonal antibody. It has an engineered Fc portion of the antibody with 2 amino acid substitutions that increase the binding affinity of the antibody to Fc gamma receptors on effector cells, like NK [natural killer] cells and macrophages. Tafasitamab leads to NK cell mediated antibody-dependent cellular cytotoxicity [ADCC], macrophage-mediated antibody-dependent cellular phagocytosis [ADCP], and direct cell death. Those are the mechanisms of tafasitamab being able to kill malignant B-cells. What is the rationale for combining tafasitamab with lenalidomide? Well, lenalidomide stimulates proliferation and activation of NK cells, and by itself can cause direct cell death of lymphoma cells. The thought behind this is that perhaps the activation of NK cells by lenalidomide, combined with the powerful initiation of antibody-dependent cellular cytotoxicity from tafasitamab, would lead to a synergistic combination.

Indeed, in vitro, the combination of tafasitamab plus lenalidomide does increase NK cell-mediated ADCC compared with tafasitamab alone. These factors led to the rationale to combine these 2 agents in patients with relapsed lymphoma. What was the L-MIND trial? Well, this was a phase 2 study. Eligible patients had relapsed refractory DLBCL [diffuse large B-cell lymphoma] and had been treated with between 1 to 3 prior regimens. The study excluded primary refractory DLBCL, which was initially defined as a case that relapsed within 3 months of R-CHOP [rituximab, cyclophosphamide, doxorubicin [hydroxydaunomycin] vincristine (oncovin), prednisone], but subsequently defined as within 6 months of R-CHOP. By the phase 2 design, all patients were treated with the same combination of tafasitamab plus lenalidomide. Lenalidomide was dosed at 25 mg orally on days 1 through 21 of a 28-day cycle.

Tafasitamab was given weekly for the first 3 cycles; these are 4-week cycles. There was an additional loading dose on day 4 of cycle 1. After 3 months, the schedule changed to every other week. After 1 year of combination therapy, the lenalidomide was discontinued and patients continued maintenance tafasitamab—again, every other week—administered intravenously. The primary endpoint of the L-MIND study was overall response rate. Eighty-one patients were enrolled and treated. They had a median age of 72 years, and the median number of prior therapies was 2. About half of the patients had received only 1 prior therapy; it is important to keep that in mind. Because this combination can be used either in the second-line for patients for whom you know will be transplant ineligible, or in the third-line setting and beyond for patients who have relapse after transplant, or, again, in patients who are not transplant eligible. Only 11% of the patients in the study had received prior transplant.

The results reflected that the combination achieved an overall response rate of 59% and a complete response rate of 41%. The median duration of response was very impressive at 35 months, and the median progression-free survival was 16 months. Overall survival was reported as almost 3 years at 32 months. Toxicities of the combination most commonly observed included neutropenia, which was grade 3 or 4 in almost half of patients. Febrile neutropenia occurred in 12% of patients. Thrombocytopenia was also seen, as were rash, diarrhea, and fatigue, much of which may be from the lenalidomide.

The combination is well tolerated, but 18% of patients experienced serious events. Infusion reactions with the antibody are not common, but not unheard of. About 6% of patients had grade 1 infusion reactions. There were no serious infusion reactions. Lenalidomide was reduced—not infrequently, as you can imagine—with 25 mg being the starting dose, although many patients were able to stay on at least 20 mg or higher. That's a summary of the L-MIND trial and the recent approval of tafasitamab and lenalidomide.

John Burke, MD, reviews the practical implications and role of tafasitamab and lenalidomide in addition to reviewing significant results from the L-MIND trial.

L-Mind Trial and Implications for R/R DLBCL

 What are the current guidelines for second-line therapy for patients who are not eligible for transplants, such as the patient that I have described? Just to outline the management of second-line patients who have relapsed diffuse large B-cell lymphoma [DLBCL] —the first order of business is to determine whether patients are eligible for transplant or not. That is not always completely clear from the day that you see the patient and that your perception of their transplant eligibility may change as you treat them. Maybe they have improved performance status as you go along For the most part, however, you can determine that relatively early. For patients who are eligible for transplant eligible, the standard of care remains: administer a salvage chemotherapy regimen followed by autologous stem cell transplant. That is based on old data from a trial called the PARMA study, demonstrating that autologous stem cell transplant improves overall survival when compared with just conventional chemotherapy.

Patients who are ineligible for transplants have a wider variety of options, one of which is a conventional chemotherapy regimen, such as the combination of rituximab, gemcitabine, and a platinum agent. In more modern times, we now have a couple of newer regimens that are available for patients like that, one of which is the combination of polatuzumab, bendamustine, and rituximab. This was initially FDA approved as a third-line therapy, but NCCN [National Comprehensive Cancer Network] guidelines have now incorporated it as an option for patients as second-line therapy. Indeed, patients in the second line were studied in the clinical trial and demonstrated clinical benefit with that regimen. A third option for patients who are ineligible for transplant is tafasitamab and lenalidomide, and this is an option for second-line therapy and beyond. For third-line therapy, the preferred approach for most patients is CAR [chimeric antigen receptor] T-cell therapy. There are now three CAR T-cell products on the market that are approved for patients with experience with at least 2 prior regimens. Patients who are not eligible for CAR T-cell therapy can be treated with any of the options listed previously, such as pola-benda-rituximab [polatuzumab vedotin plus bendamustine and rituximab], tafasitamab and lenalidomide. Alternatively, these patients can receive a novel agent, Selinexor or they can receive conventional chemotherapy. Exactly how to sequence all those options is not known—there really is not a clear best way to sequence all those treatments.

What percentage of patients relapse or refractory to frontline treatment? About a third of patients will relapse or have primary refractory disease. The majority of these are relapses and not primary refractory. I will point out that not everyone who has a positive PET scan at the end of therapy definitely has persistent disease. There was interesting data from a trial called the REMARC trial that demonstrated that, of the patients who achieved only a partial remission by PET scan at the end of induction, only about three-quarters of those patients eventually progressed. That is, about one-quarter of those patients converted to complete responses with no additional therapy. If you have an end-of-treatment PET scan that is abnormal, you definitely want to confirm with a biopsy that that patient has persistent active lymphoma before you commit that patient to additional treatment. As I said, perhaps one-fourth of positive PET scans turn out not to truly reflect residual disease.

John Burke, MD, considers factors for initiating second-line treatment in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

Second-line Treatment Recommendations for R/R DLBCL

 What frontline treatment options are available for patients? Well, of course, the standard of care, as all of you know, for the management of diffuse large B-cell lymphoma [DLBCL] is R-CHOP [rituximab, cyclophosphamide, H – doxorubicin (hydroxydaunomycin) vincristine )oncovin), prednisone] chemotherapy. The large majority of our patients get that treatment. Certainly, there are exceptions. For example, in the cases of our older patients, some of them may have impaired performance status or comorbidities that prevents the administration of full-dose R-CHOP. Those patients may be treated with reduced doses, or the so-called R-mini-CHOP regimen [rituximab and reduced-dose CHOP]. Patients who have severe cardiac impairments may not be able to receive any doxorubicin at all. For those patients, an alternate regimen might be considered, such as a substitution of etoposide for the doxorubicin. There is not really a single standard of care for patients who are not eligible for R-CHOP, and we know from many series that those patients tend to receive a mixture of different regimens. As I mentioned before, patients with double-hit lymphoma and triple-hit lymphoma fare poorly with R-CHOP and they have high rates of relapse. Phase 2 studies have demonstrated improved outcomes using more intensive chemotherapy regimens in those patients.

Although no randomized Phase 3 trial has proven a benefit to such intensive regimens, most institutions and experts now recommend more aggressive regimens for those patients with double-hit or triple-hit lymphoma. Examples of such regimens include the dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen or R-hyper-CVAD [rituximab and cyclophosphamide, vincristine, adriamycin [doxorubicin], and dexamethasone] at some institutions. In clinical practice, one question that comes up is, should we wait on the FISH [fluorescence in situ hybridization] results? I am in a community practice, and the turnaround time for FISH in my hospitals is a couple of weeks sometimes; our pathologists do not do FISH locally. We send it out to a central lab, and it is not uncommon for it to take about 2 weeks to come back. Typically, the time between the diagnosis of lymphoma and the time I get the FISH back is more than 2 weeks. That is, we see the patient, and we get a staging PET scan and a CT scan. We may need a bone marrow biopsy, and then we get the drugs authorized. We teach our patients about treatment. That whole process typically takes me approximately 2 weeks. 

By the time I initiate the therapy, I usually have the results of FISH test back. Occasionally, though, I need to move things more quickly and treat patients in the hospital. For those patients, I will sometimes start chemotherapy before the FISH result is back. If it happens that I have started someone on R-CHOP and the result comes back that they have a double-hit or a triple-hit lymphoma and I want to use a more aggressive regimen, that is fine. I just switch them to the more aggressive regimen for cycle 2.

What typically is the response rate and duration of response after R-CHOP? Most studies show that the overall response rate for R-CHOP chemotherapy for patients with DLBCLs is between 75% and 90% with complete remissions achieved in between 55% and 70% of patients. 3-year progression-free survival is generally reported at about 65% to 70%. For all-comers, we generally think that we cure diffuse large B-cell lymphoma with R-CHOP in about 60% of patients.

John Burke, MD,  discusses frontline treatment options for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

Frontline Treatment Options for R/R DLBCL

 Hello, everyone. My name is John Burke from Rocky Mountain Cancer Centers. I'm Associate Chair of the Hematology Oncology Research Program at US Oncology. We are going to be talking today about diffuse large B-cell lymphoma [DLBC]). I will be presenting a case of an older patient with relapsed diffuse large B-cell lymphoma, and we are going to talk about the treatment options available in this rapidly changing field. To start with the case, we have a 76-year-old man who presents with a right inguinal mass and has constitutional symptoms of fatigue and loss of appetite. This man has a past medical history of atrial fibrillation and hypertension. On the physical exam, you notice a 5-cm right inguinal mass, bilateral axillary lymphadenopathy, and splenomegaly. His performance status is a 2, and the laboratory workup is notable for the measured hemoglobin of 9.9. The patient undergoes an excisional biopsy of the lymph node that shows a diffuse large B-cell lymphoma, a germinal center B [GCB] subtype, and it is is CD20-positive. A FISH [fluorescence in situ hybridization)] panel for aggressive lymphoma mutations demonstrates a 14 to 18 translocation affecting 

This is not a double-hit lymphoma. You perform a PET scan and a CT scan on him that demonstrates diffuse lymphadenopathy as well as splenomegaly. He does not have extranodal disease other than the spleen, and you elect to forego a bone marrow examination because it does not appear suspicious on the PET scan and a CT scan. Based on all this, the patient is classified as having a stage III diffuse large B-cell lymphoma. You calculate his IPI [International Prognostic Index for Diffuse Large B-cell Lymphoma] score; we will assume that it is an intermediate-risk group. You initiate standard treatment with 6 cycles of R-CHOP [rituximab, cyclophosphamide, doxorubicin (hydroxydaunomycin) vincristine (oncovin), prednisone] chemotherapy and he achieves a complete remission. Everything is going fine.

However, 1 year later, he presents with recurrent axillary lymphadenopathy. You biopsy this lymph node, and it confirms a relapse of his GCB subtype diffuse large B-cell lymphoma. Based on his age—the patient being in his late 70s—and his relatively mediocre performance status, you have determined him to be ineligible for high dose chemotherapy and autologous stem cell transplant. Rather than initiate a salvage regimen like ICE [ifosfamide, carboplatin, etoposide] or something similar, you decide to initiate a novel therapy of tafasitamab plus lenalidomide.

That is the case. Before we talk about the treatment, we will go back and talk about risk assessment for diffuse large B-cell lymphoma and prognostic factors. Of course, when you are assessing a newly diagnosed patient with diffuse large B-cell lymphoma, the most important prognostic model is the International Prognostic Index, which looks at 5 factors: if the patient’s age is greater than 60 years, their performance status, their LDH [lactate dehydrogenase] levels being above normal or not, the number of extranodal sites being 2 or more versus 0 to 1, and the stage. Another factor that affects prognosis is the cell of origin.

We know that, as a general rule, patients with germinal center B subtype have a more favorable prognosis than those with the activated B-cell subtype as determined by gene expression profiling. In clinical practice, we do not do gene expression profiling routinely. It is not a widely available test. We replace that, typically, in our pathology labs with an algorithm like the Hans algorithm where immunohistochemical staining serves as a substitute for gene expression profiling. Another factor that is important is the presence or absence of a combination of 

Patients who have 2 of those are diagnosed with double-hit lymphoma, and those diagnosed with 3 of those have triple-hit lymphoma. Patients with double or triple-hit lymphomas have, of course, a less favorable prognosis when treated with conventional R-CHOP than those with DLBCLs that are not double-hit or triple-hit lymphomas.

John Burke, MD, presents a case of a 76-year-old man with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

John M. Burke, MD | Authors

Articles

Clinical Pearls for Managing R/R DLBCL

Novel Therapies for R/R DLBCL

L-Mind Trial and Implications for R/R DLBCL

Second-line Treatment Recommendations for R/R DLBCL

Frontline Treatment Options for R/R DLBCL

Case Presentation: Diffuse Large B-cell Lymphoma