The question often comes up: What percentage of patients are refractory or relapse after standard frontline therapy? Depending on the risk category, this could be as high as 30% or 35% of patients who initially respond to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and then relapse, or a primary refractory. Primary refractory disease is fairly rare, probably less than 5% of patients. But it does occur, and it typically results, or is manifest by, a positive PET [positron emission tomography] scan or a progressive disease during primary care for your R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. The more common scenario, which is going to occur in about up to a third of cases, is relapse after achieving a remission. Usually those relapses occur in the first year or 2 after completion of primary therapy.

For the patient with refractory/relapsed lymphoma, these patients can receive salvage chemotherapy and then high-dose therapy and transplant. The question is, is that who can qualify for this? Well, for the patients who are in first relapse and have chemotherapy-sensitive disease—the more chemotherapy sensitive, the better—reaching a PET-negative prior to high-dose therapy and transplant clearly has an impact. The issue here is that some of these patients are not great candidates for transplant high-dose therapy, but also some of these patients do not respond well to the second line. The primary refractory patients and the early relapse do very poorly in that setting. So this is not something that we actually recommend necessarily.

When you look at the overall in a patient in the R-chemotherapy [rituximab chemotherapy] era, the outcome of patient after high-dose therapy and autologous stem cell transplantation is still in the range of only 10% to 15% of the patients that you save. This is not the perfect option at this point, but thankfully we have other options we’ll talk about, including cell therapy.

The patients who are eligible for transplantation are really an unmet need. Similarly, so are the patients who fail after transplantation. There is some option now, so we’ll talk about CAR T [chimeric antigen receptor T cell] and cell therapy in a minute. But it may be easier to use. The polatuzumab data refer to BR [bendamustine, rituximab], which was very impressive and is approved. It was 40 patients per arm, but the CR [complete response], which was the primary end point, was 40% versus 15% and with a very significant difference in duration of response and survival. This is interesting. The R2 [lenalidomide, rituximab]–ibrutinib is something that we presented updated at ASH [American Society of Hematology Annual Meeting] in a non–GC [germinal center] subtype. It’s important because we go with age: Up to two-thirds of elderly patients, over 70 and above, can be ABC [activated B-cell] or non-GC subtype, so this is really 1 of the unmet needs we alluded to before.

For these patients, R2 [lenalidomide, rituximab]–ibrutinib, during the chemotherapy-free part, we had a response rate of 60% and some very durable response. Patients were well over 3 years with the disease control with R2 [lenalidomide, rituximab]–ibrutinib, particularly in a non-GC diffuse large cell lymphoma. This is something to keep in mind. Finally, there are the L-MIND data, which is lenalidomide plus anti-CD19, tafasitamab, and the response rate in this situation was also very impressive and very durable. This is really potentially an option and that has been combined in a frontline setting in the context of BR/POLA [polatuzumab], or bendamustine-rituximab and POLA [polatuzumab], so we’re trying to integrate this novel therapy in the frontline setting.

In patients who are not candidates for transplant, this is really again an unmet need. Those are perfect candidates for clinical trials, and we’ll talk a little more about cell therapy in that setting. But in reality, the patients who are truly not eligible for autologous stem cell transplant because of frailty or comorbidities are not going to be necessarily great candidates for CAR T cell, at least at this point.

What’s a typical response and duration of response after R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]? This is a challenging question, and it all depends on where you get the data. If we talk about outcomes in real life, the R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] outcomes are worse, as opposed to clinical trials in which there is an inherent selection bias. We tend to select the healthier and less sick patients in trials, so they will probably tolerate better the treatment and they will complete the treatment, and also patients will have less aggressive disease.

In general, what I see in my general practice is about 60% to 70% of patients are cured with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]; the rest, 30% to 40% of patients will either relapse or remain refractory. In terms of long-term remission, probably the most important data that we have is on the GELA [Groupe d’Etude des Lymphomes de l’Adulte] study, the French study that compared R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] versus CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], that showed that about 50% of patients were still alive at 10 years’ follow-up.

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R/R DLBCL: Transplant Eligibility and R-CHOP

The treatment factors that affect newly diagnosed patients with newly diagnosed diffuse large B-cell lymphoma [DLBCL] include pretty standard clinical features, including age, functional status, and comorbidities. From the perspective of the disease, if the patient has double-hit lymphoma, that can also impact treatment selection.

For the majority of patients who have reasonable performance status, if they’re in their 60s or 70s and don’t have significant comorbidities, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is still going to remain the standard in the current era outside clinical trials. If they have significant advanced age in their 80s or late 70s, comorbidities, or really poor performance status starting with less inventive regimens such as mini-R-CHOP [reduced-dose regimen of rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or just palliative treatment with steroids, Rituxan, and cyclophosphamide, or vincristine, like R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] is often used in that setting, that’s appropriate.

Again, for most fit patients who can receive R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], that’s still the standard outside double-hit lymphoma. As we discussed, if a fit patient has double-hit lymphoma, that’s when a more intensive regimen is usually offered.

The stage of diffuse large B-cell lymphoma can impact treatment to a certain extent. Most patients are going to be advanced stage, with stage III or IV, depending on the extent or absence of extranodal disease. Again, for those patients, 6 cycles of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is still standard therapy.

In the case of limited stage—so a true stage I—there are data from recent trials that show for low-risk early stage patients, it’s appropriate to offer either 3 or 4 cycles of systemic therapy with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], sometimes followed by radiation. Increasingly we’re seeing data that suggest that if you achieve a complete metabolic response, for instance, after 3 cycles of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], completing systemic therapy with 4 cycles and omitting radiation is still reasonable and achieves very good outcomes for early stage, stage I or II, DLBCL.

For germinal center or nongerminal center, which is said to be activated B-cell subtype, there have been a number of trials over the past decade that have attempted to improve the outcome of patients with higher-risk, nongerminal center, DLBCL, which usually has an activated B-cell phenotype. Investigators have attempted to introduce proteasome inhibitor bortezomib, lenalidomide, BTK [Bruton tyrosine kinase] inhibitors such as ibrutinib. To make a long story short, all these trials have not been positive.

Despite the significant biological rationale for introducing targeted agents for these subtypes of patients, particularly the ABC [activated B-cell] subtype, none of the studies has panned out. Some of this may be related to patient selection in terms of not getting the higher-risk patients on the studies. Another part of this is likely that the method of assigning subtypes has been too crude, and we really need to move to a more advanced molecular testing method to discriminate the subtypes and then assign targeted agent pathway inhibitors, targeted agents in those specific pathways for those specific subtype.

This is an important aspect. When you see patients having comorbidities and cardiac issues, neurological issues, etc, we know that this is a difficult situation. The definition is the geriatric assessment, but basically if it’s an older patient, more than 80 years old and with some comorbidities, you can use an attenuated form of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], which is the mini-CHOP [reduced-dose regimen of cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. That could be very helpful. If the patients have cardiac dysfunction, we can replace the doxorubicin with etoposide or gemcitabine, or liposomal doxorubicin. Sometimes bendamustine–Rituxan [rituximab] will be used, sometimes combinations with antibody-drug conjugates that are being looked at in the frontline setting. Hopefully other combinations will emerge as a possibility.

In patients who are older, it’s important to mention here—the patients that are older, frailer, a bit but not necessarily cardiac dysfunction—1 thing that works really well is to give them somewhat of a prephase with vincristine, rituximab, and steroids for 5 days. Then they come back a week later and then we can get them started on R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. These patients do really well.

There’s finally novel therapy, as I mentioned, that might offer an opportunity to replace chemotherapy in that setting. There are the R2 [lenalidomide, rituximab]–ibrutinib data from The University of Texas MD Anderson Cancer Center, from the SMART START trial from Jason Westin. That has shown very high response rates and CR [complete response] rates after an induction that is basically nonchemotherapy option: response rate of 80% and CR over 36%. These patients can receive an abbreviated course potentially of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] if they’re elderly. As I alluded to the polatuzumab, POLA, is used in the relapsed/refractory setting. We’ll talk a little later about this, but it is going to be integrated as well as bevacizumab is integrated in a frontline setting. We are building up by adding these types of therapy that might allow us to treat, even better, these patients who have comorbidities and issues that prevent them from using anthracycline.

Newly Diagnosed DLBCL: Treatment Decision Factors

We know large cell lymphoma is the most common lymphoma, about one-third of the cases. We know that over 50% of patients can be cured with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] chemotherapy, about 20% to 30% relapse and 10% to 15% suffer primary failures. The real challenge is that these failures occur in 80% of the cases—80% of these relapses occur in the first 18 months, and they usually are very challenging to administer salvage therapy, even with high-dose therapy and transplant. Therefore, this is very important to try to have markers that help us identify, prognosticate, and stratify patients.

I would say there are 3 types of factors, and they are the lymphoma factors: We know large cell lymphoma is a very heterogeneous entity and primarily large cell lymphoma, for example, is a separate subtype. But under the NOS [not otherwise specified] subtype of large cell lymphoma, there’s a different molecular subtype, the non–GC [germinal center]. But well beyond that, now we know that 7 factors are very important, unique BCL2, double expresser, double-hit lymphoma. Beyond the FISH [fluorescence in situ hybridization]—typically the definition is by FISH—there’s about 50% of these high-grade double-hit lymphoma that have a rare, poor prognosis with standard R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] that have the signature of a high-grade lymphoma but do not have the FISH by gene expression profiling. 

 next-generation sequencing is not done yet in routine. But we try to narrow down a molecular subtype.

Then there’s the tumor burden of the lymphoma, and the stage, the LDH [lactate dehydrogenase], bulky, and the baseline metabolic volume if you want to go by PET [positron emission tomography] scan. The second aspect that was developed is a prognostic model trying to put this in context, and we have revised IPI [ipilimumab] in the RQ era. We have the NCCN [National Comprehensive Cancer Center] IPI [ipilimumab] guidelines trying to use the same factors basically, the basic factors of the IPI [ipilimumab], but 25 is better, the age and the LDH and try to identify better smaller subset, particularly on the extreme, the very good-risk and the very high-risk patients.

There is something that is interesting called the PFS [progression-free survival] 24—no failure after 2 years; therefore the PFS 24 name. These patients do very well, similar to the control population that never have lymphoma. To identify these factors, there’s the IPI [ipilimumab] 24. There’s a calculator available online that also uses similar factors where it adds gender, bulky disease, and lymphocyte count at baseline. There’s another factor to take into account the diagnostical delay to start treatment versus immediate treatment, which obviously the patient started within 2 weeks. Those who start later usually have more symptoms.

That’s really important because these factors that are clinical factors are centrally based on the characteristics of each patient that have been very helpful, but not really to predict the long-term outcome or to predict the response to a therapy. There are some host factors that we heard about regarding gender. Comorbidities we’ll talk more in a minute, but there are a number of factors not yet used in practice: the class II MHC [major histocompatibility complex] expression; the beta-2 microglobulin, which is a class I molecule; microenvironment signature inflammation; cytokine; vitamin D. This is obviously growing, and those are more the host factor, and this again predicts for DFS [disease-free survival], PFS, and survival but not for the early failures, which is the real problem that I mentioned before.

Finally, the response to therapy is the PET scan. And the interim PET scan, although it is debated, when it’s a negative PET regardless of the stage, even in advanced stage, this is usually a very good outcome. Sometimes there’s nonspecific inflammation and residual gray zone like PET scan with low SUV [standardized update value], and what matters is the delta, the drop of the SUV. Typically in routine what we really look at is the patient who has a negative PET scan at the end of treatment. That was very predictive.

Here I just want to mention that when someone has a PET scan that is positive, it’s important to biopsy this patient. We need to know if it’s truly active disease because it has some hot spots. Finally I think there is another factor emerging, and that will take more role in the future on prognostic factor, the DNA, or cell-free DNA that is detectable in all patients at baseline, regardless of the stage. It reflects the tumor genetic makeup or signature profile if you want. Studies, not large studies but very impressive, show that patients who are PET negative and cell-free DNA negative after 3 cycles do remarkably well.

This is a number of factors. How do we use this in practice, so in a frontline setting, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] has remained the default, but it’s not sufficient for high-risk patient, double-hit, and double expresser, and non-GC lymphoma. But it’s important to understand that we can start to adjust with the treatment. In a non-GC subtype, so far the attempts to do R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] have not really panned out. Patients, about one-third of these non-GC double expresser, and we know that they do very poorly with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], so we try to give them something more intensive. Finally, in the high-grade lymphoma that I mentioned, these guys do very poorly with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], and there’s definitely no standard therapy. We tend to use, if you’re a younger patient, the EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride] regimen. That’s the impact, in a nutshell, of these prognostic factors in lymphoma.

The question is, what is the prognostic and predictive significance of DLBCL [diffuse large B-cell lymphoma] genetic signatures The management of DLBCL has evolved over the years. While next-generation sequencing has shown valuable information, there is an absence of a specific drug or medication that will target this specific gene signature. Its application in routine clinical practice remains elusive, in my opinion. However, it underscores the fact that there’s a need of developing trials using this genetic testing. One of the challenges I see using these tools, like next-generation sequencing, is the cost, the availability, and especially reproducibility, that it will be difficult for physicians who are not familiar with this testing to maintain their patients.

DLBCL Risk Assessment and Genetic Signatures

 We learned about diffuse large B-cell lymphoma over the past several years. It goes back to the recognition that really this is not a single disease entity but actually represents different types of lymphomas that collectively are referred to as diffuse large B-cell lymphoma. More specifically it’s been recognized that there is 1 type called germinal center subtype, and another ABC [activated B-cell] subtype, which have different biological features and different outcomes, with ABC subtype having the worst outcomes in germinal center subtype.

Over the past couple of years, we’ve done to identify that this is really an oversimplification of the subtyping, and with advanced molecular tests, next-generation sequencing, and high throughput genomic analysis, 2 separate groups of independently identified diffuse large B-cell lymphoma as really having a number of different subtypes. Germinal center is actually going to be divided into 2 different groups: worse and better outcomes. Similarly, ABC subtype can be divided into at least 2 or more subgroups, some of which have better outcomes than others.

From a practical perspective, I would say in 2020 to really approach diffuse large B-cell lymphoma the same way with the notable exception of double-hit lymphoma, is probably a germinal center–derived subtype of diffuse large B-cell lymphoma that tends to have a more aggressive course.

The question about initiating treatment before receiving the cytogenetic results is an important one. If you know that a patient has diffuse large B-cell lymphoma and they need immediate treatment, the standard of care still is R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and chemotherapy for frontline therapy outside of our clinical trial. If you don’t have the cytogenetic results to know that the patient takes double-hit lymphoma, it’s still reasonable if the patient has a clinical urgency to initiate treatment with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and then potentially escalate a more intensive regimen such as dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride] with subsequent cycles.

Turnaround time of getting these molecular tests back can be shorter or longer, depending on if the patient is being seen at a high-volume center or a community center. Many community centers send out the FISH [fluorescence in situ hybridization]test for the MEK, BCL2, and BCL6 translocations. And there may be a longer turnaround time. But again, I wouldn’t let that delay prevent me from initiating treatment if there’s a clinical urgency to start therapy. It’s perfectly fine to start with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and then subsequently change after you have the results of those molecular tests.

Therapy Initiation Prior to Cytogenetic Testing Results

Bradley J. Monk, MD, FACS, FACOG, co&#8208;director of GOG Partners, Arizona Oncology (US Oncology Network); professor of Gynecologic Oncology at University of Arizona, Creighton University; and medical director of the US Oncology Research Gynecology Program, discusses the FDA approval of bevacizumab (Avastin) and other novel agents in cervical cancer.

In the setting of metastatic cervical cancer, or when the cancer has spread to the lungs, liver, or lymph nodes, the standard treatment was a regimen examined in the GOG 240 trial, the results of which were published in the New England Journal of Medicine, says Monk. In the trial, patients were randomized to receive chemotherapy with or without bevacizumab. The addition of bevacizumab to chemotherapy was associated with increased overall survival, at 17.0 months versus 13.3 months with chemotherapy alone; higher response rates were also observed with the combination.

Results from this trial led to the 2014 FDA approval of the antiangiogenic bevacizumab; this was the first targeted therapy to receive approval in cervical cancer. Specifically, the indication is for bevacizumab to be used in combination with paclitaxel and either cisplatin or topotecan. Essentially, investigators took a doublet regimen in this space comprised of chemotherapy and turned it into a triplet regimen with the addition of bevacizumab, says Monk. The triplet is now the global standard and it is approved for use around the world, adds Monk. Bevacizumab was the first approved targeted therapy to receive approval in this space in the United States, and ultimately, it improves survival by around 4 months, concludes Monk.

Bradley J. Monk, MD, FACS, FACOG, discusses the FDA approval of bevacizumab and other novel agents in cervical cancer.

Bradley J. Monk, MD, FACS, FACOG, Arizona Oncology

Articles

R/R DLBCL: Transplant Eligibility and R-CHOP

Newly Diagnosed DLBCL: Treatment Decision Factors

DLBCL Risk Assessment and Genetic Signatures

Therapy Initiation Prior to Cytogenetic Testing Results

Dr. Monk on the Significance of Bevacizumab in Cervical Cancer