BTK Inhibitors, PI3K Inhibitors, and CAR T-Cell Therapy Shake Up Hematologic Malignancies Armamentarium

Harry Paul Erba, MD, PhD, spotlights practice-changing data that emerged in recent years in hematologic malignancies and speaks to remaining questions, particularly with CAR T-cell therapy, in each paradigm.

BTK inhibitors, PI3K inhibitors, and CAR T-cell therapies have changed the treatment landscape of many hematologic malignancies, said Harry Paul Erba, MD, PhD, who added that the evolving paradigms underscore the need for individualized decision making to ensure patients receive the most appropriate regimen for their disease, as well as the correct supportive care and necessary dose adjustments.

For example, in chronic lymphocytic leukemia (CLL), findings from the phase 3 ELEVATE-RR trial (NCT02477696) represented the first head-to-head results comparing ibrutinib (Imbruvica) with acalabrutinib (Calquence) in patients with previously treated disease. The noninferiority trial demonstrated similar progression-free survival (PFS) with both BTK inhibitors; however, acalabrutinib was associated with a lower frequency of common adverse effects (AEs), grade 3 or higher AEs, serious AEs, and treatment discontinuations from AEs vs ibrutinib.

“For patients starting a new BTK inhibitor for CLL, this study suggests that starting with a second-generation drug, such as acalabrutinib, may be in the patient’s best interest to avoid serious toxicities like atrial fibrillation and hemorrhage. However—and I have patients like this in my own clinic—patients who are already responding to and tolerating ibrutinib should not switch from ibrutinib to a second-generation drug based on these data,” said Erba, an instructor in the Department of Medicine and member of the Duke Cancer Institute at Duke University School of Medicine, in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on leukemia and lymphoma.

The virtual meeting covered key updates in CLL, as well as mantle cell lymphoma (MCL), Hodgkin lymphoma, follicular lymphoma, and marginal zone lymphoma (MZL).

In the interview, Erba, who chaired the event, discussed the takeaways from his colleagues’ presentations given during the meeting, spotlighted practice-changing data that emerged in recent years in hematologic malignancies, and spoke to remaining questions, particularly with CAR T-cell therapy, in each paradigm.

OncLive®: During the IPC meeting, Andrea Sitlinger, MD, of Duke Cancer Institute, discussed the data generated with BTK inhibitors in CLL. What are some of the most important updates to emerge for patients with CLL?

Erba: The most important update in CLL was [regarding] the studies that randomly assigned patients to ibrutinib, which is the first-in-class BTK inhibitor, vs a second-generation BTK inhibitor, either acalabrutinib or zanubrutinib [Brukinsa]. The takeaway for me [from those studies] is that the efficacy of these [second-generation] BTK inhibitors is very similar to ibrutinib, but the toxicity profiles are different.

Ibrutinib is associated with more cardiac events, such as atrial fibrillation. There may have been a hint of more bleeding events as well [with ibrutinib vs acalabrutinib and zanubrutinib], although that was difficult to tease out based on how the data were collected and how the [bleeding events] were graded. However, certain toxicities were more common with [acalabrutinib and zanubrutinib] [vs ibrutinib], such as headaches. When we talk about chronic therapy that is going to [be given] for a long time, even grade 1 and 2 toxicities can become old for patients.

I’m a firm believer that once a patient is on a targeted therapy and responding, their dose should be modified, and their symptoms should be managed as appropriate to maintain that response before switching [to another agent]. There is no guarantee that when we switch a patient to another drug, they will tolerate it any better than the drug they had been on.

It comes down to a very similar discussion that we have had with our patients with chronic myeloid leukemia [CML]. We shouldn’t just be switching from one drug to another as soon as a patient has a toxicity. Rather, we should try to manage those toxicities through supportive care and dose adjustments.

How did the data from the 5-year analysis of the phase 3 iNNOVATE trial (NCT02165397) add to the understanding of the utility of ibrutinib plus rituximab (Rituxan) in patients with Waldenström macroglobulinemia?

The data [from the iNNOVATE trial] were very positive for using [ibrutinib plus rituximab] in patients with Waldenström macroglobulinemia. [The combination] is an oral therapy. The choice between these different agents comes down to, again, toxicity profiles, as well as dosing, food restrictions, and proton pump inhibitor [PPI] restrictions. These are all [factors] that we have to consider with patients.

I have patients who can’t live without their PPI, which can be an issue when we are talking about chronic therapies. For some of these patients, twice-daily dosing can become an issue. It’s great that our patients have choices.

In thinking about Waldenström macroglobulinemia, I was impressed with the data showing the activity of BTK inhibitors. [The field is] trying to avoid what I used to do when I was [taking care of more patients with] lymphoma, such as fludarabine and bendamustine. [We are now] trying to get away from intravenous chemotherapy and move toward oral therapies.

Matthew McKinney, MD, and Ahmed Galal, MD, FRACP, MSc, both of Duke Cancer Institute, highlighted the roles of BTK inhibitors and CAR T-cell therapies in MCL. How have these options changed the treatment landscape for this patient population?

In MCL, it is important to focus on the goals of therapy from the start, which reminds me of where things in acute myeloid leukemia [AML] have been. What are the goals of therapy? Are we talking about a patient who is younger with very few comorbidities? [In those situations,] maybe we can think about a potentially curative approach, or an approach with time-limited therapy that allows a patient to get into a deep response that can [translate to] a very long PFS.

I wouldn’t forget about treatments like high-dose cytarabine-based regimens in MCL. When I was taking care of more patients with MCL, I often used the Nordic regimen, but there are other regimens now that just focus on the high-dose cytarabine component. Then, [we can think about] autologous stem cell transplant [ASCT] as an option.

What is wonderful is that we now have oral therapies available for patients [with MCL] that are quite effective, including BTK inhibitors. These agents can be used in patients who have relapsed, in older patients who may not be able to tolerate intensive chemotherapy, or in those who have short remissions after therapy. That is where the advances have been made.

In MCL, we need to sort out where treatments such as CAR T-cell therapies fit in. Many of us have the sense that the efficacy and toxicity profile of CAR T-cell therapy will be enhanced by moving it sooner into therapy, maybe even for the treatment of minimal residual disease. Studies that look at positioning CAR T-cell therapy vs transplant after initial intensive therapy or salvage therapy need to be prioritized.

Dr. Galal also discussed the current treatment of patients with Hodgkin lymphoma based on data from the phase 3 ECHELON-1 trial (NCT01712490). Where does brentuximab vedotin (Adcetris) fit into the Hodgkin lymphoma paradigm?

The focus in Hodgkin lymphoma is with the data surrounding the use of brentuximab vedotin in patients receiving doxorubicin, vinblastine, and dacarbazine [AVD]. [During the IPC meeting], several [points] came out in our discussion, including some questions from the audience about whether there are regimens that we would consider in place of AVD plus brentuximab vedotin.

The answer I heard was that, at this point, we should prioritize brentuximab vedotin with AVD [vs AVD plus bleomycin] in patients [with Hodgkin lymphoma], avoid bleomycin, and manage the neuropathy and myelosuppression that can be seen with that regimen. This should be prioritized even in older patients.

Another question was: What do we do in younger patients with poor-risk disease? Do we think about dose-escalated bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]? There we have a clear divide that we call the Atlantic Ocean. In Europe, especially Germany, dose-escalated BEACOPP is used more vs in the United States, where we try to avoid agents that have been associated with a higher risk of secondary malignancies like myelodysplastic syndrome and AML.

The question becomes: What is the true benefit of brentuximab vedotin with AVD vs ABVD? Ahmed Galal, MD, FRACP, MSc, of Duke Cancer Institute, made a very strong point in avoiding bleomycin, so bleomycin may be able to be dropped from the ABVD regimen after the first few cycles of treatment, especially if the patient achieves a PET-negative response. Patients can avoid some of the cumulative toxicity [associated with ABVD that way]. However, as he pointed out, bleomycin toxicity can occur with the first dose of treatment, so it does not completely [mitigate] the risk. [Avoiding bleomycin] is really an advantage of [adding] brentuximab; [patients may be spared] the pulmonary toxicity associated with bleomycin.

The second benefit I see with the brentuximab vedotin plus AVD regimen is when we look at a patient’s requirement for intensive therapy, such as conditioning or preparative regimens, followed by ASCT, it was much less with the use of brentuximab vedotin plus AVD vs ABVD. That really gets at this whole [point] that we saw a PFS benefit [with brentuximab vedotin plus AVD vs ABVD], but not a survival benefit.

What does that mean for patients? In oncology, survival benefit is of critical importance. However, I would not discount PFS. This is true in AML where I spend much of my time, but also in Hodgkin lymphoma, where we have to think from a patient’s perspective about what comes next? If a patient has relapsed or refractory disease and progresses, we are talking about a palliative regimen or moving to intensive chemotherapy followed by ASCT and all the risks associated with that, including the long-term risk of myeloid malignancies after ASCT.

The data showed a lower use of intensive regimens in patients who received brentuximab vedotin plus AVD vs ABVD. That is what I was thinking in terms of an improvement in PFS, but it was good to see the data. Most patients would see [getting less intensive therapy] as an advantage even though it is hard to get drugs approved in oncology now based on PFS, outside of multiple myeloma.

What novel agents have transformed clinical practice in AML?

I usually spend my time [taking care of patients with] AML, which is becoming a chronic illness. In acute leukemia, we are victims of our own successes early on. We can give younger patients intensive therapy and transplant with curative intent. Yet, the majority of patients [are not eligible for that approach]. We are held to the criteria that [AML] is a curable disease, but unfortunately, for most patients it isn’t.

In our own clinics, a lot of us are seeing that we can maintain patients on different therapies over time with BCL-2 inhibitors, FLT3 inhibitors, and IDH inhibitors. Multiple myeloma has led the way, but we hope we’re catching up.

Finally, Alexandra Stefanovic, MD, of Duke Cancer Institute, spoke to treatment options in indolent lymphomas, such as follicular lymphoma and MZL. What key updates have been observed regarding the treatment of patients with these diseases, particularly with PI3K inhibitors?

PI3K inhibitors have a checkered past in indolent lymphoma. Specifically, we all remember the studies that were done with the agents in CLL that reflected signals for colitis and pneumonitis. It is now good to see that although those signals are still seen, the newer PI3K inhibitors have a much lower incidence [of those toxicities]. That was news to me because a lot of time we hear a soundbite from a long time ago and forget that the field has moved on. There is still room to attack that pathway.

Responses [have been observed with PI3K inhibitors] across the board in MZL, follicular lymphoma, and [other] indolent lymphomas. One question I posed [during the IPC meeting] was that although responses were seen across the board, the most durable responses were seen in the MZL [cohort]. I wondered if there was a biologic reason [for that]. We felt that it was maybe because those patients [with MZL] had fewer prior therapies going into the study.

That might explain it, but on the other hand, the treatment of MZL has fallen behind others, right? We have so many options for follicular lymphoma, CLL, and Waldenström macroglobulinemia, but MZL is a rare entity in which we hope to get by with rituximab and CD20-directed antibodies for a while to avoid systemic chemotherapy. The PI3K inhibitors allow us to think about oral therapies sooner for patients with MZL who would have been getting intravenous chemotherapy.

What have been the most noteworthy data to recently emerge in the realm of hematologic malignancies? How are remaining questions being addressed?

The biggest update has been with the comparison of ibrutinib and acalabrutinib [in CLL]. We saw similar efficacy but a different toxicity profile [between the agents]. We need to understand the data and how to use it. As initial therapy, a lot of CLL clinicians are starting with acalabrutinib; however, thinking about the twice-daily dosing requirement and [the need to] avoid PPIs with acalabrutinib may be an issue for some patients. We saw less cardiac toxicity with acalabrutinib vs ibrutinib, but other toxicities, such as headache, are seen more frequently [with acalabrutinib]. Ultimately, having options for patients continues to be very important.

The second takeaway is that [we don’t fully know] where CAR T-cell therapy is going to land in lymphoma. We know it is active and leads to a long disease-free survival. However, it has significant toxicity, especially in patients with active disease.

Something I didn’t get a good answer to [at the IPC meeting] and that continued to confound our community colleagues is: When do we send patients for CAR T-cell therapy evaluation? I put forward a message as the moderator. In a patient for whom we are thinking about using a salvage therapy with a BTK inhibitor or lenalidomide [Revlimid] plus rituximab, although we can see responses, they aren’t durable. When we are moving on to those regimens, that is when we should get patients into a program that has cellular therapy, whether it be transplant or CAR T-cell therapy. That way those options can be [a possibility].


  1. Byrd JC, Hillmen P, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2021;39(suppl 15):7500. doi:10.1200/JCO.2021.39.15_suppl.7500