Individualized Care Drives Treatment Focus in AML, DLBCL, and CLL

Ehab Atallah, MD

Future advances in leukemia and lymphoma treatment will arise from careful consideration of current management strategies, explained Ehab Atallah, MD, who emphasized the importance of framing future directions around present unmet needs, such as relapses after later-line CAR T-cell therapy.

“We are in a fortunate place where we have many good options [for patients with lymphoma and leukemia], and now we are looking at adverse effects and quality of life, determining what will keep our patients safest and maintain their responses for the longest possible time,” Atallah said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on leukemia and lymphoma, which he chaired.

In the interview, Atallah, a professor of medicine and section head of hematological malignancies in the Medical College of Wisconsin Division of Hematology and Oncology, as well as a specialist in leukemia and myelodysplastic syndromes at Froedtert Hospital, discussed key points from each presentation shared at the meeting. He noted how patient characteristics influence current treatment strategies in acute myeloid leukemia (AML), and how frontline pirtobrutinib (LOXO-305), a novel BTK inhibitor, may move toward use in chronic lymphocytic leukemia (CLL). Atallah also highlighted the growing evidence favoring CAR T-cell therapy as an effective treatment option in CLL.

OncLive^®: Your colleague, Karen Carlson, MD, PhD, of Froedtert Hospital and the Medical College of Wisconsin, spoke about AML management. When choosing an up-front treatment for patients with AML, what factors help guide that decision?

Atallah: Many different factors [should be considered]. First, when we look at a patient, we look at how fit they are, whether they can handle intensive chemotherapy. We ask: What is the goal? Is the end goal transplant? If so, can this patient handle a transplant?

Then, we look at the disease itself and the different mutations, prognostic factors, and cytogenetics. By putting [those fitness and molecular factors together], and [considering] the patient’s social support, we are able to decide on the next step, [which is] the best choice of therapy, for each patient. Sometimes, [this process is] straightforward. Sometimes, it remains a gray area, overall. What is amazing, however, is that we have all these available options now, and we can greatly improve the prognoses for our patients.

Could you expand on some of the options for up-front treatment in AML?

We have many options. If the patient is fit, you could consider intensive chemotherapy, [including combining it] with antibodies like gemtuzumab ozogamicin [Mylotarg], or FLT3 inhibitors such as midostaurin [Rydapt]. If the patient is unfit for chemotherapy, we could consider hypomethylating agents in combination with venetoclax [Venclexta], or in combination with ivosidenib [Tibsovo], which was recently approved.

Sumana Devata, MD, of Froedtert Hospital and the Medical College of Wisconsin, presented on advances in the treatment of relapsed/refractory diffuse large B-cell lymphoma. What are some emerging treatments for this patient population?

I specialize in leukemia, so it was nice for me to watch the progress that is happening in lymphoma with all the antibodies that are currently available for patients that are much better tolerated than prior chemotherapy or prior intensive chemotherapy. Even in the lymphoma world, if a patient is fit, and they can handle that intensive chemotherapy, you could consider chemotherapy. However, the other antibodies that have recently been approved also lead to good results and excellent tolerability.

Guru Murthy, MD, of Froedtert Hospital and the Medical College of Wisconsin, spoke about CLL treatment. Currently, options such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) have been either approved or given National Comprehensive Cancer Network indications. What factors go into choosing 1 of those BTK inhibitors?

In CLL, we are very fortunate to have that many choices for BTK inhibitors, which are great drugs. Now, we can be picky with which 1 to choose. Obviously, you should choose 1 that has good efficacy and the least amount of adverse effects (AEs). The newer BTK inhibitors, such as acalabrutinib and zanubrutinib, seem to have less overall AEs compared with ibrutinib. However, ibrutinib still has the longest follow-up that we currently have.

Another BTK inhibitor, pirtobrutinib, is currently under investigation in clinical trials. What is the potential future for this agent in CLL if it continues show positive data and eventually gains approval?

You could consider pirtobrutinib as the new kid on the block. [The agent] has a slightly different mechanism of action and works where other BTK inhibitors do not: where there are mutations. It will be interesting to see where pirtobrutinib goes. Will it move to frontline therapy? Will it move to frontline therapy in combination with BCL-2 inhibitors? We are looking forward to the data to see how this drug develops.

Nirav Shah, MD, of Froedtert Hospital and the Medical College of Wisconsin, spoke about CAR T-cell therapy in CLL, a disease in which this kind of therapy had yet to be approved. What could potentially happen to change that and make that modality a potential option for this population?

Although CAR T-cell therapy is still not approved for patients with CLL, we know it is quite effective. Overall, looking at the data together, about 50% of patients who are resistant [to prior therapy] end up responding to CAR T-cell therapy. [That being said, the future of CAR T-cell therapy is still unclear]. Because [CLL can cause] long-term hypogammaglobulinemia [that poses a] potential risk for infections, CAR T-cell therapy is a good option for patients who are refractory to BTK inhibitors and BCL-2 inhibitors.

As CAR T-cell therapies move up in the treatment paradigm, 1 of the challenges that Dr Shah talked about was how to treat patients who do not respond or who relapse or recur after that therapy. How could this challenge potentially be addressed across leukemia and lymphoma?

Relapses post CAR T-cell therapy will be interesting to see develop. Currently, most patients who get to CAR T-cell therapy, at least those outside of clinical trials, have been primary refractory, making them difficult to treat. If CAR T-cell therapy moves up front, [and can be used in] patients who have not received prior therapies, there is a good chance that they will be able to respond to conventional treatment or targeted therapy after CAR T-cell therapy. It will be interesting see how the field develops from there.

Dr Shah also discussed some other emerging CAR T-cell therapies, such as [CAR-engineered natural killer (NK) cell therapies] and CD22-directed CAR T-cell therapy. How could those therapies potentially add on to the traditional CD19-directed CAR T-cell therapies that are already approved?

The addition of NK or other antigens that will be used for CAR T-cell therapy will be interesting. We already have CD19 antibodies, CD20 antibodies, and bispecific antibodies. Having a different target may allow for more patients to respond. Some leukemias downregulate the CDs on the outside; there is a chance that these patients would not respond to CAR T-cell therapy.

The other option is the NK cells. Having an off-the-shelf option is priceless because for many patients who receive CAR T-cell therapy, there is a gap between collecting and modifying the T lymphocytes. If we can eliminate that gap, many more patients will be able to receive CAR T-cell therapy, and hopefully, benefit from it.

What ongoing research regarding leukemia and lymphoma is happening at Froedtert Hospital and the Medical College of Wisconsin?

We have multiple ongoing studies. As Dr Shah mentioned [in his presentation], we have a double CAR T-cell therapy, and he is also working on developing a triple CAR T-cell therapy.

Regarding bispecific antibodies, we have a study using CD3 and CD38, which is expressed in AML and ALL, looking at patients with relapsed/refractory disease. We also have other studies combining lintuzumab, a radioactive conjugate antibody, with CD33. We are actively researching immunotherapy to see whether we can improve the outcomes of patients with acute leukemia in general.

What main message would you like to leave with colleagues regarding the ongoing developments and research in leukemia and lymphoma?

There is a lot going on. As leukemia and lymphoma specialists, we all need to be aware of the new findings and all the research that is [being done]. It is getting to be so much, which is great. Conferences like this [IPC meeting] help us highlight a few things using short talks with specific focuses to bring [all this information] forward. It is going to be important for us to continue to [share the evolving findings with each other to improve outcomes].