Atallah Breaks Down Key Advances Made Across Leukemias and Lymphomas

Ehab Atallah, MD

The combination of venetoclax (Venclexta) plus azacitidine (Onureg) in acute myeloid leukemia (AML), novel obinutuzumab (Gazyva) combinations in chronic lymphocytic leukemia (CLL), studies with blinatumomab (Blincyto)/TKI regimens in acute lymphocytic leukemia (ALL), and TKI discontinuation in chronic myeloid leukemia (CML), are among the most exciting recent advances made in the realm of leukemia/lymphoma treatment, according to Ehab Atallah, MD.

“We had 4 leukemia [and lymphoma] experts discuss updates on 4 different [diseases]. These are really important updates shared in short talks where we educated our colleagues on what’s new [during an] online [meeting], so it was very accessible,” Atallah said. “[Staying up-to-date] on the [latest data] is very useful.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on leukemia and lymphoma, Atallah, a professor of medicine and section head of hematologic malignancies in the Department of Hematology and Oncology at Medical College of Wisconsin, spotlighted recent updates, emerging approaches, and next steps for research in leukemia and lymphoma.

OncLive®: What practice-changing data read out last year for the treatment of AML?

Atallah: The phase 3 VIALE-A study [NCT02993523] randomized patients to receive azacitidine [Onureg] alone vs azacitidine plus venetoclax. [Data from this trial marked] a significant improvement for the treatment of patients with AML. Participants did well [with the combination], which resulted in increased complete remission [CR] rates. We also learned from that study that [patients whose tumors carry] some specific mutations, such as IDH1/2, respond well to the combination of azacitidine and venetoclax. I would consider this one of the major practice-changing studies that we have had in the past 5 years, possibly even decade, in AML.

The phase 3 QUAZAR AML-001 study (NCT01757535) was another important study to read out in this disease. Data from this trial led to the FDA approval of oral azacitidine as a maintenance treatment. What were the clinical implications of this decision?

This study enrolled patients who had intermediate- or high-risk AML, although most enrolled [fell into] the intermediate-risk group. After receiving induction and consolidation [therapy], patients were randomized to maintenance or no maintenance with oral azacitidine. The drug was given 2 weeks on and 2 weeks off until disease progression or intolerance. Patients tolerated [the treatment] quite well. The maintenance [treatment resulted in a] prolongation of the overall survival [OS] and event-free survival [EFS].

Based on [those findings], oral azacitidine was FDA approved for [use as] maintenance [treatment]. I would really like to emphasize that oral azacitidine is not [the same as] intravenous azacitidine. [The] dosing and pharmacokinetics [between the 2 approaches] are different. [As such,] they cannot be used interchangeably at this moment.

What are some of the efforts being made to further leverage agents like venetoclax to improve outcomes for these patients? Are 3-drug regimens under investigation?

After the FDA approval of venetoclax for use in combination with azacitidine or decitabine or low-dose cytarabine in the frontline treatment of patients [with] AML, multiple studies are [evaluating the addition of] other drugs to this combination to improve survival for this group of patients. We will, of course, need to balance that [efficacy] with toxicity. [However], clearly, venetoclax has changed the treatment landscape for AML.

Shifting to CLL, what are some emerging approaches that are gaining momentum?

In CLL, over the past 5 or 7 years, [we have seen a] marked improvement in treatment. [It’s amazing to] consider how many patients are alive now because of the BTK inhibitors and the BCL-2 inhibitors that are currently available. Now, [we are excited about the] combination ofBCL-2 inhibitors with BTK inhibitors. With this combination, almost 70% to 80% of patients achieve a status of undetectable MRD, which is quite impressive. We will see what this combination does in the future.

Additional phase 3 data with novel venetoclax combinations have recently been reported, as well. What should be taken away from these updates?

[We saw] recent updates from 2 studies: the phase 3 CLL14 trial [NCT02242942], which [examined] obinutuzumab plus venetoclax in the up-front setting, and the phase 3 MURANO trial [NCT02005471], which [examined venetoclax and rituximab (Rituxan)] in the relapsed/refractory setting.

In those studies, [among the] patients who achieved an undetectable MRD level, approximately 80% stayed in remission [and did not need] treatment with 4 to 5 years of follow-up. [We also saw that] patients with high-risk disease, such has those who with a 17p deletion, complex chromosomes, or unmutated IGHV, did not fare as well as those who did not have high-risk cytogenetics. Still, this group of patients [represents] an unmet need, and we need to improve treatment for [them].

Considering what has been learned thus far about achieving undetectable MRD, what is the role of this biomarker in practice? How are you using it to inform clinical decisions?

Achieving undetectable MRD has been shown over and over in CLL to be very important prognostically in EFS, and in some studies, for OS. Also, the duration of time that patients stay off treatment, for example, using a BCL-2 inhibitor with venetoclax, is very significant and guided by the presence or absence of MRD. In the near future, we will make our decisions by trying to get patients to an undetectable MRD [status], so they can stay off of treatment and do better in the long term.

What are the latest developments that have been occurred in the ALL treatment paradigm? What are some of the efforts being made to reduce the use of chemotherapy-intensive approaches?

In adult ALL, [we have seen] multiple improvements, especially [with regard to] immunotherapy. Inotuzumab ozogamicin [Besponsa], which is a conjugated CD22-targeted antibody, and blinatumomab, which is a bispecific antibody against CD19. Both of those [agents] have really changed the treatment landscape in relapsed/refractory ALL, and we [anticipate the same benefit] in the up-front setting.

A recently completed trial [NCT02013167] randomized patients to chemotherapy alone or chemotherapy with blinatumomab; we are waiting for those results. [Another] ongoing [study is randomizing] adolescent and young adults to chemotherapy only or chemotherapy plus obinutuzumab; we are also [anticipate] those data.

Blinatumomab [in combination with] the TKI dasatinib [Sprycel] has been shown [to have] amazing efficacy in patients with Philadelphia chromosome [Ph]–positive ALL. With this combination, almost 80% [of patients] achieved a CR and stayed in remission with a short follow-up of 1 to 2 years. We really believe that in the future, this combination will replace chemotherapy.

Also, an ongoing cooperative group trial is comparing blinatumomab with a TKI vs chemotherapy with a TKI, and we [are excited to see] what those results will show. Finally, we cannot ignore the [advances made with] CAR T cells, and how well patients do in the relapsed/refractory setting [with this approach]. Patients are achieving MRD negativity [with this modality]. Of course, we need to wait for more long-term data with that treatment.

You mentioned some of the novel approaches being explored with blinatumomab. What patient subsets derive the most benefit from this agent?

[We know that] blinatumomab has [demonstrated] efficacy in the relapsed/refractory setting; it has also shown even better efficacy in the setting of MRD. If patients have no morphological evidence of disease and have MRD detectable by flow cytometry or by clonoSEQ testing, they do remarkably well with blinatumomab. Even in patients who [have] persistent MRD in first remission, giving blinatumomab at that point brings into question whether those patients should proceed to stem cell transplantation or not. In that field, in the up-front [setting, and] in the Ph-positive ALL group, [the agent has yielded] remarkable improvements [in outcomes].

Moving to advances made in CML, a key area of focus right now is focused on the potential for TKI discontinuation. Which is known thus far about this?

In CML, the current focus is to get patients off drug. There are multiple benefits to getting patients off [of these agents]. First, patients on a TKI do have reduced quality of life [QoL]. For those patients, we [see what we consider to be] mild adverse effects [AEs] of diarrhea and fatigue. However, [if on continuous treatment, patients can experience] these toxicities for the rest of [their] lives; as such, they really should not be referred to as mild.

The second benefit [to discontinuation] is economic. TKIs are very expensive. At least 50,000 patients are alive with CML in the United States, [and these drugs] cost about $100,000 per year; that is close to $4 to $5 billion. [As such, discontinuation is] not only an economic benefit to society, but to patients because they have co-pays that they are worried about. [They are also] worried [when they move] from job to job; [they are concerned about whether] their insurance will cover their medication or not.

Lastly, multiple studies dating back to 2010 have enrolled thousands of patients have shown that it is safe to attempt a treatment-free remission in those patients. The possibility of stopping a TKI is very important, even for younger patients and children. You can imagine, keeping a 12-year-old or a 14-year-old with CML on a TKI, or any drug for that matter, up until they are 60 or 70 years of age is not ideal in terms of QoL. We do not know what the very long-term AEs would be [of doing this, either].

How do you approach monitoring your patients after they stop TKIs?

With stopping TKIs, we [need] patients who fit [certain] criteria. Mainly, patients [must be] in CML chronic phase, and they need to have been on drug for at least 3 years and have sustained a deep molecular response for at least 2 years, which is a level of a BCR-ABL of less than 0.01%.

In those eligible patients, the chances of having a successful treatment-free remission is about 50%. Once patients attempt to stop a TKI, monitoring for them occurs monthly for the first 6 months, every 2 months for 18 months, and every 3 months [thereafter]. The reason the monitoring is more intensive up front is that most patients who have a molecular recurrence, [experience this] in the first 6 months.

We also need to be aware of, and let our patients know that, when they discontinue the drug, we discontinue at the level of MR4 or 0.01% or they could have undetectable BCR-ABL. However, we only restart [treatment upon the] loss of major molecular remission [MMR] or [if they have] a level of more than 0.1%. It is very important to tell our patients that so that we can reduce their anxiety—[this is] especially [important to communicate] when the BCR-ABL becomes detectable after stopping [treatment in] someone who previously had undetectable BCR-ABL.

What are some of the data that have read out to support TKI discontinuation?

In patients who are eligible, the success rate [of TKI discontinuation] is about 50%. There have been multiple studies using different TKIs in different parts of the world, with more than 2000 patients enrolled. It is surprising how close the chances of a successful treatment-free remission is that in all of these studies; it really varies from 40% to 60%. In the LAST study [NCT02269267], which was a large US study that included patients [on different] TKIs—[it did] not [look at] just 1 TKI—the chances of a successful treatment-free remission was about 60%.

The concern of progression to accelerated phase or blast crisis has essentially been [examined in] case reports in these 2000 patients, [and the chance of that happening] is less than 0.5%; that is actually very similar to what has been reported overall for patients who remain on a TKI. There really is no increased risk, that we know of, to attempt a treatment-free remission.

You mentioned that efforts need to be made to better understand the long-term AEs associated with TKI discontinuation. What are some of the AEs that are typically seen and how do you manage these patients?

[In terms of] the AEs that patients could experience, there is such a thing as withdrawal syndrome. Patients develop joint pain, which is mainly in the hands [and in] most it will resolve by 6 months. Supportive care using nonsteroidal anti-inflammatory drugs or acetaminophen [Tylenol] is indicated. Very few patients need to restart the TKI because of how significant that pain is. I personally [have] restarted [treatment in] a patient when their pain lasted for 3 or 4 months, and it was just so severe that we tried steroids and we were at the point of narcotics.

The second AE, [or challenge], is the need to come into [the clinic] to get labs done. As I mentioned, labs need to be done monthly for the first 6 months, every 2 months for 18 months, and every 3 months thereafter. This intensive schedule is different for patients who have been on a TKI for a long time because normally, if they are having a good response, we would do their labs every 3 to 6 months and I would see them in the clinic every year. It is a more intensive schedule of follow-up, which they are not used to—especially in the first year or 2. This was clearly highlighted during the pandemic when patients really did not want to go to any healthcare facilities. [Another consideration] is the anxiety that a patient experiences when they come in to get the labs checked once a month to see whether they are going to relapse or not [and whether] they need to restart the treatment.

What is your advice for optimally supporting patients through this process?

In patients who need to restart the treatment, it is very stressful because it is almost like having leukemia all over again, in patients’ own words. Explaining to the patients about the withdrawal syndrome, the more intensive monitoring, and the anxiety associated with stopping and checking labs is important so that you can support [them] during the attempt for treatment-free remission.

Looking at some of the different TKI options in the paradigm, bosutinib (Bosilif) is the latest to come on the market. How does this drug measure up with other available options?

Bosutinib is a TKI that works very similarly to that of imatinib [Gleevec], dasatinib, and erlotinib [Tarceva], [although it has] a different AE profile. Bosutinib was the last to come on the market, at first in the relapsed/refractory setting, and then in the frontline setting. [The agent] is taken once daily with food [and is] well tolerated, overall. The main AEs [experienced with] bosutinib [include] liver function abnormalities, skin rash, and diarrhea. The diarrhea may be quite intense up front but slowly resolves after.

[The agent can be administered in] 2 ways. You [could] start with the full dose, which, for the frontline setting, is 400 mg. Then, you would tell the patient that for the first week or 2, the diarrhea may be significant but it [will get] better. The alternative is to slowly escalate the dose from 100 mg to 200 mg, 300 mg, and 400 mg, until you get to the full dose. That way, [you are] preventing the patient from experiencing significant diarrhea and being discouraged from continuing the drug.

In terms of efficacy, compared with imatinib, [the data with bosutinib are comparable to what] we have seen with the other second-generation TKIs; there is no difference in OS, but patients do achieve faster and deeper remissions with a second-generation TKI compared with imatinib.

What has been your experience with patient adherence to this drug?

Overall, [patients can adhere] to bosutinib because it is a drug that is given once daily, and [despite toxicities like] diarrhea and liver function [abnormalities], it is well tolerated. We also know from multiple phase 3 trials of the TKIs compared with imatinib that, at the end of the day, about 65% of patients stay on the TKI they started with. [This can be] because of AEs or because of response. At the end of the day, [only] one-third of patients change the TKI they started with.