Erica DiNapoli

Although the role of immunotherapy has been revolutionary in the field of oncology, not all patients will respond to treatment, according to Natalie I. U. Vokes, MD, who added that modeling approaches must be used to integrate biology into more accurate predictive biomarkers of response to this approach.

“We're still in the early phases of this research; however, we’re starting to gain insight on the biology of which patients respond to immune checkpoint inhibitors. Better understanding the biology will help with the development of new biomarkers,” explained Vokes. “Even so, we must be cautious in terms of how we apply the biomarkers that we currently have. We need to continue to stress the importance of this biology–biomarker interplay because that will help us treat as many patients as possible with these therapies.”

, Vokes, a medical oncology fellow at Dana-Farber Cancer Institute, discussed the rise of predictive genomic biomarkers in oncology.

: What is the role of genomics in predicting response to immune checkpoint inhibitors in oncology?

 The biomarker that is brought up most often is tumor mutational burden (TMB); as a biomarker, I believe this is somewhat limited. TMB is not a strong discriminator between responders and non-responders to this therapy. In clinical practice, when we think about using TMB [as a biomarker], we have to be cognizant of the fact that we're choosing between specificity and sensitivity; there's always going to be that trade-off. However, this doesn’t mean we shouldn't use TMB; we just need to be cognizant when doing so.

More broadly speaking, I believe TMB is interesting. Even though it imperfectly segregates between responders and non-responders, it does track this. I believe this points to the fact that we don't fully understand the biology behind TMB; there are many nuances to that association.

It’s important to remember that there’s a difference between biomarker and biology. We've spent a lot of time trying to jump immediately to the use of biomarkers but there's still a lot that we don't understand about biology. Once we better understand biology, we can better develop these biomarkers. Rather than going straight toward the use of single biomarkers, such as TMB or PD-L1, we could potentially use modeling approaches to integrate this biology into more accurate predictive models [for response].

Could you expand on what is known about TMB? Are any other markers on the rise?

TMB is probably the most well developed in this field. Reflecting back on early studies, many used whole exome sequencing and looked for genomic correlations. These studies indicated that the TMB in patients who responded to therapy was often higher than in those who did not. This was initially demonstrated in the melanoma space. Since then, it has been confirmed with several other sequencing techniques in an array of disease contexts.

Notably, on June 16, 2020, the FDA approved pembrolizumab (Keytruda) for the treatment of patients with unresectable or metastatic solid tumors that are TMB-high in the second-line setting.So TMB is [involved in an important] FDA approval.

Other biomarkers are not as well developed. In the lung cancer space, 

 mutations come up quite often. However, I believe 

 is generally a poor prognostic marker across different treatment settings. There's also some other work showing that the presence or absence of other mutations, such as 

 mutations are, but we still have a lot to learn.

In lung cancer, we tend to use driver mutations as biomarkers like 

; those patients tend to not respond as well [to this treatment]. We also have to be careful that we don't extend this to all driver-altered non–small cell lung cancer because 

 might be biologically different. There’s still a lot for us to learn about these biomarkers.

What work is being done to effectively predict response to immunotherapy?

We wanted to apply the framework of precision medicine to immunotherapy and, traditionally, that consisted of finding a single genomic alteration or a single gene, which then would allow us to effectively predict whether a patient will respond to therapy. However, those therapies also have a different mechanism.

Immunotherapies are much more complicated, and the landscape of what determines whether a patient is going to respond is complicated. It may not only be determined by the genomics of the tumor itself; we may need to incorporate additional immune features.

With this said, the analysis of single genes is very interesting because it helps us understand how tumor pathways can affect the immune response to the tumor. However, from a biomarker standpoint, we're probably going to need to have some kind of approach that integrates some of these features into a more complicated model.

Where should future research efforts be focused?

Comprehensively aggregating molecularly characterized patient cohorts is a current limitation in this space. I believe working together as a community, bringing together as many samples as we can, and continuing to conduct molecular profiling of these samples is important, as we move forward with this research.

Traditionally, a lot of our work was focused on whole exome sequencing and genomics; however, I believe integrating additional molecular assessment profiles, such as multiplex immunohistochemistry, transcriptomics, and newer approaches, will help enrich the search [for biomarkers] in this space, allowing us to look for more of these associations.

What does the future look like for genomic biomarkers in oncology?

We hope to continue incorporating as many different data types as possible, ultimately, applying more sophisticated modeling techniques. This will help us better understand the biology and will help us build new predictive models. I foresee this being an iterative approach that we can then apply to different data sets in different treatment contexts. Ultimately, this will help us identify some of the differences that exist in terms of how patients respond in the first- and second-line settings.

Articles

Natalie I. U. Vokes, MD, discusses the rise of predictive genomic biomarkers in oncology.

Vokes Voices How to Use Genomics to Predict Response to Checkpoint Inhibitors in Cancer

The approval of belantamab mafodotin-blmf (Blenrep) addressed an unmet need in relapsed/refractory multiple myeloma, according to Sagar Lonial, MD, FACP, and to build off the efficacy observed with the agent, research efforts are dedicated to examining its use in other novel combinations and moving it earlier on in the treatment journey.

“BCMA is the ‘it’ target of 2020,” said Lonial, a professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine. “Belantamab mafodotin provides an off-the-shelf [opportunity] to target BCMA; the agent not only elicits responses in a highly-resistant patient population, but these responses are also durable. The agent also has a reasonable safety profile.”

(NCT03525678) served as the basis for the August 2020 FDA approval of the antibody-drug conjugate (ADC) in the treatment of patients with relapsed/refractory disease who have received 4 prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.

Updated data from a 13-month follow-up analysis presented during the 

showed an overall response rate (ORR) of 32% (97.5% CI, 21.7%-43.6%) in patients who received the recommended 2.5 mg/kg dose of belantamab mafodotin and an ORR of 35% (97.5% CI, 23.9%-46.0%) in those who received the 3.4 mg/kg dose of the agent.

“Several combination studies [with belantamab mafodotin] will emerge,” said Lonial, who is also the chief medical officer of Emory University’s Winship Cancer Institute. “The is whether we should use a different dose or schedule to be able to combine [the ADC] with additional agents. There is also a big push to use the agent up front in combination with the 3-drug induction regimen of lenalidomide, bortezomib, and dexamethasone (RVd).”

, Lonial discussed the role of belantamab mafodotin in relapsed/refractory multiple myeloma and emerging BCMA-targeted agents that are generating excitement in this setting.

What is the significance of the regulatory approval of belantamab mafodotin in multiple myeloma?

 Belantamab mafodotin provides patients with a new treatment modality, particularly those who have exhausted most [available] treatment approaches. Despite all the great advances that we've seen, with median overall survivals now exceeding 10 to 12 years, there are patients who become triple-class refractory; these patients are resistant to IMiD, PIs and anti-CD38 antibodies and. For these patients, treatment options are relatively limited.

Could you shed light on findings from the

phase 2 DREAMM-2 trial that served as the basis for the approval of this agent?

In this randomized phase 2 trial, [investigators] evaluated 2 different doses of belantamab mafodotin. The lower dose of 2.5 mg/kg, which is now the FDA-approved dose, was requested by the [regulatory agency] to see whether it would have a different safety profile.

Although on the surface it appeared that the response rates were somewhat similar, and the adverse effects (AEs) were somewhat similar [between the doses], results showed that more patients had grade 1/2 AEs versus grade 3/4 AEs [with the lower dose]. The ORR was 32% with a median progression-free survival (PFS) of 2.9 months and a DOR of 11 months [in those who received this dose]. The DOR truly showed that in the patients for whom this therapy appears to be working, you can safely keep them on this agent despite the AEs that occur.

Could you speak to the administration of this agent along with the safety profile?

Belantamab mafodotin is an intravenous BCMA ADC. The agent is administered intravenously, and it is very well tolerated from an infusion reaction perspective. The ADC is much easier to give with acetaminophen and Benadryl prophylaxis; it doesn’t require steroid premedication. The agent doesn't take very long to administer and is given every 3 weeks.

The safety profile has 2 [notable toxicities]. The first is hematologic toxicity; we have seen suppression of the white blood count and some level of anemia; a lot of that is often disease related but it can be attributed to belantamab mafodotin, as well. The second is keratopathy, which is the development of microcysts within the cornea. Notably, microcysts occur in about 70% of patients who receive belantamab mafodotin.

Notably, only about 50% of patients are symptomatic and the most common AE was dry or itchy eyes, which can be addressed with lubricating eyedrops. People are most worried about changes in visual acuity; however, only approximately 20% of patients on the trial experienced these changes. The optimal way to administer belantamab mafodotin is by partnering with an ophthalmologist, who can see the patient before each dose is given to ensure that the keratopathy is not significant or severe enough that it does warrant adjustment or holding of to allow for that [toxicity] to improve.

Are there any other elements of the trial that you wanted to elaborate on? What was the significance of this research?

This trial addressed the unmet medical need in myeloma. Patients had received a median of 6 prior lines of therapy, and both 100 patients were on each arm [of the trial]; thus, it provided a fairly robust experience.

I believe it reflects the real-world practice of seeing patients with triple-class refractory multiple myeloma. It’s important to remember that, just because patients develop keratopathy, doesn't mean it will always impact their vision. In patients who have changes in visual acuity, the median time to recovery is about 22 days, so missing a dose could allow for them to recover back to baseline.

Moreover, in the majority of patients who had to miss a dose or reduce their dose, the disease actually didn't grow out of proportion. Over 80% of these patients maintained their disease response or deepened their response, likely because of the very long half-life of the antibody. It's a different drug in a number of different ways than most are used to dealing with.

What are the next steps for research with this agent?

As with every drug that we use in myeloma, we often try to move these agents [to examine their use] earlier on in the course of disease; these trials are currently ongoing. For example, the DREAMM-6 study combined bortezomib (Velcade) with belantamab mafodotin and demonstrated a significantly high ORR with a similar keratopathy rate to what was shown in the DREAMM-2 study. 

Other ongoing are trials examining belantamab mafodotin in combination with new immunologic targets. Some are looking at belantamab mafodotin in combination with 

With quadruplet therapies emerging in the frontline setting, have sequencing strategies been impacted? Do you foresee the ADC being used in second-line setting?

Quadruplet therapies are being used more frequently in the newly diagnosed setting, particularly for patients who are transplant eligible. I do foresee antibody strategies, other than daratumumab, potentially moving into the second-line setting.

The strategy at Emory University’s Winship Cancer Institute is to use daratumumab with RVd in the first 4 cycles of therapy, but not after transplant. In those cases, the use of daratumumab after transplant, is a reasonable approach, especially in the context of relapse. If you’re giving continuous daratumumab, [investigators will start to examine] belantamab mafodotin, isatuximab (Sarclisa), or other antibodies more frequently in first relapse.

What are some of the other BCMA-targeted therapies that are currently under investigation?

Belantamab mafodotin is an ADC and others are currently under development. Additionally, we have seen a lot of data on BiTEs. [With regard to BiTEs], AMG 420 led the way early on, but there are now 

targeting BCMA that have a longer half-life. Also, [data with] bispecifics have been reported by several companies. At higher doses, there seems to be ORRs ranging anywhere from 60% to 90%; this is very exciting, especially for relapsed/refractory multiple myeloma where we have been worried about T-cell health being a limiting factor for the efficacy of these bispecifics. However, this does not appear to be the case in small phase 1 studies.

Compared with lymphoma and chronic lymphocytic leukemia, we have been behind with regard to CAR T-cell therapy. [We know that] CAR T cells elicit high ORRs and minimal residual disease negativity rates along with longer DOR and PFS. The product that is furthest along in research is probably idecabtagene vicleucel. We're hoping that [this product] will be approved in the next few months based on results from the 

. Right behind this are other products that seem to have similar efficacy. We’ll have to see more information on PFS to determine which of these CAR T-cell products are optimal.

One of the differences between myeloma CARs and CD19 CARs has to do with both efficacy and toxicity. We see much less grade 3/4 cytokine release syndrome with myeloma CARs as well as less grade 3/4 neurotoxicity. This is great, because those toxicities are challenging to deal with; this differentiates CD19 from BCMA as a target.

How do you plan on sequencing these BCMA-targeted therapies?

We are often asked whether we plan on sequencing these agents. Which one will we give if we can only give one? In reality, we're going to end up giving multiple. Having off-the-shelf options is really important, particularly for older or frailer patients or those who present with acute relapse and action needs to be taken immediately.

The CAR T-cell approach may be more effective in younger patients and I suspect that we'll be giving more than one of these BCMA-targeting drugs to patients. Most trials excluded prior BCMA exposure from enrollment but, with belantamab mafodotin, we are going to be able to see whether patients who progress on a CAR T-cell therapy will respond to the ADC. For patients who respond to belantamab mafodotin and have progressed, can they respond to a CAR T-cell therapy or a BiTE? The next year will be filled with many of these anecdotal examples that will hopefully provide us with a sense of how best to sequence or if all can be used in a given patient.

Lonial S, Lee HC, Badros A, et al. Pivotal DREAMM-2 study: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma refractory to proteasome inhibitors, immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs). 

. 2020;38(suppl 15):8536. doi:10.1200/JCO.2020.38.15_suppl.8536

Sagar Lonial, MD, FACP, discusses the approval of belantamab mafodotin-blmf and how it addressed an unmet need in relapsed/refractory multiple myeloma.

Novel Combos With Belantamab Mafodotin May Move the Needle in Myeloma

Higher rates of complete remission (CR) were achieved with the addition of short-course fludarabine to ibrutinib (Imbruvica) in previously untreated patients with chronic lymphocytic leukemia (CLL), according to results from a phase 2 trial (NCT02514083) recently published in the 

In a phase 2 pilot trial, investigators set out to evaluate the combination of short‐course fludarabine and continuous ibrutinib, with the goal of debulking CLL cells as well as inducing rapid reductions in T-cell numbers.

Results showed that the overall response rate at 6 months was 93.1% with the combination. Moreover, the complete remission (CR) rate was 20.7% at 6 months, 28.0% at 12 months, and 44.4% at 24 months. Additionally, at 6 months, all evaluable patients were alive and free of disease progression. At 2 years, the estimated progression-free survival (PFS) rate was 91.3% (95% CI, 80.5%-100%), while the estimated overall survival (OS) rate was 95.8% (95% CI, 88.2%-100%).

With regard to safety, 83.0% of treatment-related adverse effects (AEs) were grade 1 to 2 in severity. The addition of 2 cycles of fludarabine to ibrutinib did not increase the risk of high‐grade hematologic toxicities or infection, according to lead author of the study Christopher Pleyer, MD. The most commonly reported grade 3 or higher hematologic AEs included neutropenia (27.6%), leukopenia/lymphopenia (31.0%), and thrombocytopenia (10.3%). Most grade 3 or higher cytopenias were associated with the addition of fludarabine; however, they were resolved with supportive care and continuously administered ibrutinib.

“The combination of ibrutinib and short‐course fludarabine appears to be safe, with no excess toxicities; particularly, there was no prolonged T-cell depletion. The combination appears to be effective, with patients achieving high rates of complete remission,” said Pleyer. “However, we need longer follow-up to determine whether these high rates of CR translate into long-term clinical outcomes, particularly improved PFS and OS.”

, Pleyer, a clinician and hematology consultant at The National Heart, Lung, and Blood Institute, further discussed the phase 2 trial examining fludarabine plus ibrutinib in CLL and SLL, the next steps for the research, and where future efforts should be focused.

 To start, what would you say has been the biggest development made in the CLL and SLL treatment paradigms in recent years?

 CLL and SLL occur predominantly in elderly patients who are in their 60’s and 70’s. In the past couple of years, we have seen tremendous advancements made in CLL. We have fantastic new treatment options available. Overall, we are moving away from a chemoimmunotherapy approach, toward a more targeted approach. The 2 most exciting drugs that are currently available for CLL are BTK inhibitors, such as ibrutinib and BCL-2 inhibitors, such as venetoclax (Venclexta).

You were the lead author of a phase 2 study that evaluated ibrutinib in combination with fludarabine in previously untreated patients with CLL and SLL. Could you discuss this trial?

In this study, we used ibrutinib as a backbone, which was already a well-established therapy for patient with CLL. The goal of the trial was to see whether the addition of 2 short courses offludarabine would improve the quality of responses in patients with CLL.

Specifically, we were looking a re-modulating the T-cell compartment with fludarabine to understand whether that adds any additional value for the treatment of [patients with] CLL. Participants started off by receiving 420 mg of ibrutinib once daily, which is the standard dose, and they continued on this therapy until disease progression or unacceptable toxicity. Fludarabine was then added during the third and fourth month of treatment. At this time, patients received 1 infusion each for 5 days. Following that, ibrutinib monotherapy was continued.

What are the findings that have read out thus far?

Two-year follow-up data are available, but we are still waiting for longer-term [results]. After these 2 years, when we did the primary efficacy analysis, we saw that 40% of patient achieved complete remission (CR) [with the combination]. Notably, this [rate] is slightly higher than what we typically see with ibrutinib as a single agent. The CR rates [with ibrutinib monotherapy are] somewhere between 15% and 20%. It’s important to note that this was not a randomized trial, and it’s difficult to compare trials, but the preliminary results did show encouraging CR rates.

The combination was well tolerated, and no additional toxicities were found. Specifically, with fludarabine, we worry about long-term depletion of T cells; however, this was not shown in the study. We also did not observe a significant increase in the number of infections.

What are some unanswered questions that still need to be addressed?

We did subset analyses of the T cells, as well. We were able to find that 2 T-cell subsets: the regulatory T cells and the follicular helper cells. These are thought to be tumor-sustaining T-cell populations that decrease during therapy. We still need longer follow-up to determine whether this translates into any clinical outcomes for patients.

This was a stepping-stone toward another study that is evaluating the addition of pembrolizumab (Keytruda) to this regimen, so a 3-drug regimen. Pembrolizumab is an immunotherapy that is frequently used in other tumor types, as well. The goal is to harness the T cells and the patient's own immune system to help them fight their cancer

Are any other CLL studies ongoing that you wanted to highlight?

A few studies are currently examining different combinations comprised of targeted drugs, specifically ibrutinib and venetoclax. These agents are already approved; however, the combination of the 2 might be more efficacious for patients. We are looking to induce a minimal residual disease (MRD)–negative state for patients [to get them] to a point where we can no longer detect CLL in the blood.

Ultimately, we hope this will bring us close to a cure, or at least a functional cure where we can limit the duration of therapy that patients receive. The current standard is to continue either of these drugs until progression. However, with the investigational combination, we may be able to provide patients with time-limited therapy.

Where should future research efforts be focused in CLL?

The study that is evaluating the addition of pembrolizumab to this regimen is important. Future research efforts should focus on finding combination therapies where we can induce high rates of undetectable MRD. The ultimate goal is to offer patients time limited therapy where they don't have to continuously take agents for their disease.

Pleyer C, Tian X, Rampertaap S, et al. A phase II study of ibrutinib and short–course fludarabine in previously untreated patients with chronic lymphocytic leukemia. 

. Published online August 18, 2020. doi:10.1002/ajh.25968

Christopher Pleyer, MD, discusses the phase 2 trial examining fludarabine plus ibrutinib in CLL and SLL, the next steps for the research, and where future efforts should be focused.

Ibrutinib Plus Short‐Course Fludarabine Elicits Encouraging CR Rates in Previously Treated CLL

The treatment landscape for acute myeloid leukemia (AML) has changed dramatically over the past 3 years, and of all the options that have become available, venetoclax (Venclexta) has had the most significant impact in the management of patients with newly diagnosed disease who are older or ineligible for intensive chemotherapy, according to Catherine Lai, MD, MPH.

“The response rates with this agent can be similar to some of our induction chemotherapy regimens; however, the toxicity profile is significantly different,” noted Lai, who added that the combination of the agent with the hypomethylating agent azacitidine led to a 34% reduction in the risk of death when compared with azacitidine alone in the phase 3 VIALE-A trial.

2020 European Hematology Association Congress

 showed that at a median follow-up of 20.5 months, the median OS was 14.7 months with the combination versus 9.6 months with azacitidine alone (HR, 0.66; 95% CI, 0.52-0.85; 

<.001); this translated to a 34% reduction in the risk of death.

The complete remission (CR) rate was significantly higher with the combination, at 36.7% versus 17.9% with azacitidine alone (

<.001). The composite CR was also higher with venetoclax/azacitidine versus azacitidine alone, at 66.4% versus 28.3%, respectively (

“We now have several new therapies in AML; some are very exciting and have shown excellent responses. Some have less efficacy and we must consider the toxicity profiles to determine whether their use is in the patient’s favor,” explained Lai. “In clinically stable patients, it's important to wait for all mutation test results to return prior to making any treatment decisions. When patients relapse, we must then repeat the mutation testing. Lastly, we must be mindful of the combinations we are giving along with [plans for] sequencing; the goal is to maximize the patient’s duration as well as quality of life.”

during the 2020 Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Lai, the director of Leukemia at MedStar Georgetown University Hospital’s Lombardi Comprehensive Cancer Center, discussed the significance of venetoclax in the AML treatment paradigm, the data from the VIALE-A trial, and remaining challenges faced in practice.

 What has been the impact of venetoclax in AML?

 The treatment landscape for AML has changed dramatically in the past 3 years. Prior to this, we were mostly using a variation of traditional cytotoxic chemotherapies. Since 2017, 8 new FDA approvals have entered into our armamentarium. Some of the most commonly used combinations consist of venetoclax with a hypomethylating agent, as well as targeted agents, such as FLT3, IDH1 and IDH2 inhibitors.

Of all the drugs that have been recently approved, venetoclax has had the greatest impact on how we treat our patients with newly diagnosed disease who are older or unfit for intensive chemotherapy.

Moreover, this agent allows for patients to be treated in the outpatient setting, which is important, especially since these patients are older and at risk for infection. This is particularly important in light of the coronavirus disease 2019 pandemic.

Could you provide some background on the VIALE-A trial?

VIALE-A is a randomized, phase 3 study comparing ventoclax plus azacitidine to azacitidine alone that followed the initial single arm trial of ventoclax plus a hypomethylating agent. Although the use of venetoclax with a hypomethylating agenthas been FDA approved, [that decision] was based on [data from] a non-randomized study. It’s important to have subsequent phase 3 data to prove efficacy.

Results from this study showed that the response rates do, in fact, hold [true] to the initial data that were presented. When you compare the 2 arms, a significant difference was observed between those in the venetoclax/azacitidine arm and those who received azacitidine alone. The CR rates were about 37% in the venetoclax/azacitidine arm compared with approximately 18% in the azacitidine-alone arm.

The composite CR rate was approximately 66% in the combination arm compared with 28% in the monotherapy arm. Notably, the median time to first response was 1 month, thus, we are seeing responses early on. It's important to do bone marrow biopsies after the first cycle of therapy to determine timing of subsequent cycles.

Furthermore, the trial showed that the duration of response [with the combination] was longer by approximately 4 months. It was very helpful that this study looked at rates of transfusion independence.

Investigators evaluated the rate of red blood cell transfusion independence and it was discovered that this occurred in about 60% of patients on the combination arm compared with about 35% of patients on the monotherapy arm. For those who aren't achieving remission but can still achieve transfusion independence, I believe that is an important end point to look at. Especially for older patients, it’s important to try to maximize their quality of life.

What does the safety profile of this combination look like?

With the combination, we are seeing prolonged cytopenias and as aresult, patients are at increased risk of fungal infections. Depending on type of anti-fungal prophylaxis used, dose modifications to venetoclax may be needed.

This is certainly a subtle nuance of the combination; oncologists who treat many leukemia patients are aware of this, because we see these patients every day. However, this is a great opportunity for local oncologists to learn how to use this combination by co-managing patients with their academic specialists.

You also mentioned that advances have been made for patients with 

 mutations. Could you expand on these new developments?

 mutations are not common in AML but there are 2 targeted agents: ivosidenib (Tibsovo) for 

-mutated disease. In general, it's important to ensure that we're getting next-generation sequencing panels on all patients as well as cytogenetics and FISH so that we can really understand the heterogeneity of the AML.

Recent data presented at ASH 2019 showed no change in OS based on time to treatment. For patients who are clinically stable, it’s important to ensure that we're waiting for mutation results to return prior to making any treatment decisions.

The VIALE-A data and the initial phase I/II study evaluated venetoclax in combination with a hypomethylating agent in a subset of patients who presented with different mutations. They specifically looked at those with 

 mutations had a significant response and did very well with the combination. I think it is important to think about how to optimize sequencing of treatment. Although many new combinations work very well, it’s important to remember that most [patients] will eventually relapse.

In your own practice, how do you choose among the available therapies?

We need to speak with our patients about their overall goals for treatment. Many new options have emerged, and this is overwhelming to patients. We should ask questions, such as whether they have a life event coming up or day to day goals, and then we can work backward to figure out the best course of therapy. Fitness is also important in AML, physiologic age plays a bigger role than chronologic age. In older patients who are ‘fit’, I tend to treat them more intensively because that can sometimes translate into a longer OS. I also look at their mutation profile since this can determine treatment options and help predict response to therapy.

There's an unmet clinical need in patients who have 

 mutations because these patients tend to be insensitive to traditional cytotoxic chemotherapy. We must seek better therapies for these patients with the goal of a sustained complete remission that will allow patients the opportunity to move onto allogeneic BMT. Two agents currently being studied in 

-mutated disease are APR-246 and magrolimab. Both appear to have very promising activity.

What challenges remain with regard to sequencing?

The main issue is that we don't know what the best sequence is yet with regard to these newer agents. We also don’t know whether combinations of novel drugs (e.g.- triplets) are superior to doublets or cetain targeted single agents because there's a risk-benefit profile in terms of toxicity. For example, if you're combining 3 drugs in the up-front setting, there's likely to be more toxicity. However, there is potential for an earlier CR or MRD-negativity, which may translate into a longer OS and hopefully better quality of life. We do not know whether giving all 3 drugs up front is the same as giving 2 drugs followed by 1 drug, or 1 drug followed by 2 drugs will have equal efficacy. We need additional clinical trials to answer these questions. 

DiNardo C, Jonas B, Pullarkat V, et al. A randomized, double-blind, placebo-controlled study of venetoclax with azacitidine vs azacitidine in treatment-naïve patients with acute myeloid leukemia ineligible for intensives therapy-VIALE-A. Presented at: EHA25 Virtual; June 11-21, 2020; Virtual. Abstract LB2601. 

Catherine Lai, MD, MPH, discusses the significance of venetoclax in the acute myeloid leukemia treatment paradigm, the data from the VIALE-A trial, and remaining challenges faced in practice.

Author | Erica DiNapoli

Articles

New content coming soon, please check back later.