Novel Treatments Begin to Rival Transplant in AML and DLBCL

Farrukh Awan, MD

The fields of diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML) are quickly expanding to accommodate novel therapies such as polatuzumab vedotin-piiq (Polivy) plus R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone), FLT3 inhibitors, and CAR T-cell therapy, treatments which may be used instead of transplant in increasing numbers of eligible patients, according to Farrukh Awan, MD.

“The biggest advance [in DLBCL] has been the development of CAR T-cell therapy for patients with early relapses with high-risk disease, which is now possibly getting into the frontline setting,” Awan said following an OncLive^® State of the Science Summit™ on leukemia and lymphoma, which he chaired.

In an interview with OncLive^®, Awan, a professor in the Department of Internal Medicine and a member of the Division of Hematology and Oncology at UT Southwestern Medical Center in Dallas, Texas, discussed key insights his colleagues shared at the meeting, including transplant and chemotherapy options in frontline DLBCL, the emergence of CAR T-cell therapy in relapsed DLBCL, and available targeted therapies in AML.

OncLive^®: Your colleague, Praveen Ramakrishnan, MD, of UT Southwestern Medical Center, gave updates in DLBCL and CAR T-cell therapy. Could you explain how autologous stem cell transplant (ASCT) may still play a role for patients in the up-front setting and what other advances are on the horizon?

Awan: There has been a tremendous advance in the field of DLBCL specifically regarding CAR T-cell therapy. We have multiple products approved for use in large cell lymphoma in the third-line setting, and in the second-line setting, and we have studies ongoing in the frontline setting. CAR T cells are the biggest advance in the field, and they are here to stay.

How will we use them? What’s the role of ASCT for patients with relapsed large cell lymphoma? That remains to be seen, as it’s a rapidly evolving field.

[Regarding] frontline treatment, [the question is:] What is the best option for frontline treatment? Historically, that had been R-CHOP therapy, and now, we possibly have polatuzumab vedotin to add to that, and that can result in improved progression-free intervals.

The argument for using [polatuzumab vedotin plus R-CHP], even if the benefit is modest, is that you want to cure as many patients with large cell lymphoma up front, because that’s the best chance that you have for your patients. [We want to be able to combine multiple options] with R-CHOP chemotherapy or similar treatments. If it cures the maximum percentage of patients, that’s what I would prefer in this setting.

That’s something that we would expect to become the standard of care in the future. We will have to wait for formal approval, but that once that is available, [we may] switch to using polatuzumab vedotin plus R-CHP. Hopefully, we will be curing a higher percentage of patients in the frontline setting.

What options are available for patients with DLBCL in the relapsed setting?

What happens when these patients relapse? Historically, the patients who had chemotherapy-sensitive disease were the patients we took to ASCT. Now, we have the option of taking them to CAR T-cell therapy, and some patients have switched completely over to CAR T-cell therapy.

I feel that there is still a role for ASCT in select patients who have disease that has come back after a few years, are still fairly chemotherapy sensitive, and are expected to do fairly well with ASCT. They don’t necessarily have to go to CAR T-cell therapy right away and can possibly save it for later.

From the real-world data we have seen, the responses and the durable remissions have been around the 30% to 40% range. We were seeing similar outcomes in patients with chemotherapy-sensitive disease beyond the first year who responded nicely to salvage therapy with ASCT. There’s still a case to be made that rather than using CAR T-cell therapy for all second-line cases, maybe we can hold off on some of those and use ASCT in some of those patients and potentially save CAR T for later. This is an ongoing debate.

We’re beginning to do CAR T-cell therapy in the frontline setting. Hopefully, the cure rates will go up and fewer patients will need any [salvage] therapy, [because we’re] curing them in the frontline setting. That’s been the biggest advance.

[There have] been a plethora of newer targeted agents, well tolerated for the most part, that have promising efficacy in the relapsed setting beyond second- or third-line treatment if the patients were not candidates for CAR T-cell therapy. Few patients are not candidates for CAR T-cell therapy. We have many drugs and options like bispecific T-cell engagers, antibody-drug conjugates, and CD19 targeting [with agents] including loncastuximab tesirine-lpyl [Zynlonta], the tafasitamab-cxix [Monjuvi] and lenalidomide [Revlimid] combination, and selinexor [Xpovio].

There are many options in the relapsed setting. Unfortunately, the number of patients who would be eligible for those therapies over CAR T-cell therapy is still small. Hopefully, we’ll cure many of our patients in the frontline setting and will not need any of these salvage therapies in the relapsed setting.

Madhuri Vusirikala, MD of UT Southwestern Medical Center, spoke about advances in AML treatments. What has the evolution of the AML therapeutic landscape looked like?

AML has been a challenging disease to treat. Historically, we had limited options for patients with this disease outside of conventional high-dose chemotherapy followed by an allogeneic stem cell transplant. Unless [patients had] a specific subset of AML, most had to undergo these treatments.

The issue with many of these agents and therapies were that patients needed to be in good shape, and they needed to be eligible for high doses of chemotherapy followed by allogeneic transplant. The availability of a donor was an issue, and older patients had limited effective options.

The biggest advance that has happened in the field has been the advent of targeted therapies. Many options that are recently approved, are in the trial process, or are at various stages of development have improved outcomes for patients with AML, especially elderly patients with AML who would not ordinarily be considered candidates for chemotherapy.

Specifically, many FLT3 inhibitors are being used with or without various chemotherapy- and non-chemotherapy–based combinations, depending on the situation. For the most part, those drugs are fairly well tolerated. They can potentially be used as disease control and a bridge to allogeneic transplant in various settings, depending on the clinical situation. FLT3 inhibitors have been a major advance in the field.

BCL-2 inhibitors and the use of azacitidine [Onureg] with venetoclax [Venclexta] and decitabine, non-conventional chemotherapeutic options, have been another huge advance. Many of our patients are now being treated with these approaches, not just the elderly, but also younger patients in certain situations where they are not good candidates for conventional chemotherapy. Venetoclax with azacitidine or decitabine has been an effective and important advance in the field.

We also have multiple other targeted therapies, specifically, IDH1 and IDH2 inhibitors. Those are seen in certain subsets and reflect back to advances in our understanding of the molecular biology of the disease. The more we understand that AML is not 1 disease, but that AML is many heterogeneous but related conditions, [the more we open] up specific targeting for specific subsets of AML.

Now we have the tools to do that. IDH1 and IDH2 inhibitors are some, smoothened inhibitors are others, and all these drugs are being combined with different chemotherapies in combination regimens. That has shown good outcomes.

What may the future bring for AML treatment?

Some of the older treatments have also now made a resurgence. For example, gemtuzumab [Mylotarg] is now making a resurgence for AML, and that’s looking promising, as expected. We also have [treatments] like [pegylated liposomal doxorubicin] along withother FLT3 inhibitors that have improved the outcomes of patients with AML.

The future is bright for patients with AML. Historically, it used to be chemotherapy and allogeneic transplant, and I feel that we can now do much better, especially for patients who would ordinarily not have good therapeutic options and would only have the chemotherapy option. Hopefully, with the advent of better understanding and the development of better products, we can narrow down and treat our patients more effectively, and hopefully have a better outcome without the use of allogeneic stem cell transplant.