A number of therapeutic approaches continue to be explored for patients with multiple myeloma, explained Larry Anderson, MD, PhD, citing CAR T-cell therapy and several combination strategies as treatments that are showing promise.

“The landscape of myeloma is constantly changing, with 12 new drugs approved since 2003 and 8 drugs approved over the past 7 years,” said Anderson. “Every year we have new drugs, and it is an exciting time in myeloma to have all these opportunities. It is also very exciting with all of the immunotherapies on the horizon.”

 on Hematologic Malignancies, Anderson, associate professor, Department of Internal Medicine, Division of Hematology/Oncology, at Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center, discussed emerging therapies for patients with multiple myeloma that were highlighted at the 2019 ASH Annual Meeting.

: What are some of the new therapies for patients with multiple myeloma?

: A lot of data were presented at the 2019 ASH Annual Meeting, and there are some recent myeloma papers were published on FDA approvals. There were some data for frontline therapies [because] that is where most of the changes are happening. Lately, some new approvals with daratumumab (Darzalex) are incorporating it into frontline therapy. Studies have looked at incorporating daratumumab into multidrug regimens in the pretransplant setting. as well, and they look very promising.

We are looking at some similar combinations with daratumumab and carfilzomib (Kyprolis) in the relapsed/refractory setting [that have led to complete remissions]. Also, there are data with bispecific T-cell engagers in heavily refractory patients. Basically, it is a way to get patients T-cell immunity without having to generate CAR T cells.

CAR T cells are very exciting, but the problem with CAR T cells is that generating cells take a month. They have to be genetically engineered and grown, and sometimes patients cannot wait 1 month for those T cells because the myeloma is growing so rapidly.

[Investigators have evaluated] an off-the-shelf molecule that helps force patients’ T cells to recognize the myeloma and attack it. Some of the research that we are doing at our institution [involves] a few CAR T-cell clinical trials for myeloma. A couple of the initial trials have shown tremendous responses and deep remissions, but it looks like many of the patients are relapsing 1 or 2 years out.

Now, there are newer trials looking at moving up CAR T-cell therapy earlier into lines of therapy, such as the second- or third-line setting. One of our upcoming trials is looking at first-line CAR T- cell therapy for patients with high-risk [chromosomal abnormalities]. Instead of waiting until relapse, these patients would be given CAR T cells instead of the autologous stem cell transplant.

We have trials looking at mutation-specific therapy, which [are] sponsored by the Multiple Myeloma Research Consortium (MMRC). MMRC has the MyDrug study, which is personalized medicine for patients with multiple myeloma.

What other studies were presented at the 2019 ASH Annual Meeting?

One of the key studies is the GRIFFIN study. That randomized study looked at up-front daratumumab with the standard triplet of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) versus RVd alone. This was for frontline pre-transplant induction in patients who were newly diagnosed with myeloma. In that study, we are seeing significantly more deep remissions and molecular remissions or minimal residual disease (MRD) negativity. However, only time will tell how that translates into progression free survival (PFS) and overall survival, but so far it is very encouraging.

Another study, the CANDOR trial, evaluated daratumumab and carfilzomib in combination with dexamethasone for relapsed/refractory myeloma. Those patients had very deep remissions as well as nice response rates, and they tolerated the therapy quite well. It was a tripling of the molecular remissions with MRD testing, and [the regimen] significantly improved PFS, which has not been reached in the daratumumab group.

What other FDA-approved agents are incorporating into your practice?

The FDA recently approved selinexor (Xpovio), which is a selective inhibitor of nuclear transport. It gives physicians an option for these patients who have failed multiple lines of therapy. It is for triple-class refractory patients who have already had an immunomodulatory agent, a proteasome inhibitor, and a CD38-targeted monoclonal antibody. It does have some tolerability issues with nausea, but as long as physicians are preemptively managing that with a very aggressive antiemetic regimen, most patients will be able to tolerate it fine and stay on therapy.

What key challenges remain in the field of myeloma?

The key one is that most patients become resistant to all of the drugs that they are treated with, so we still need more [drugs to be developed]. Also, as I mentioned previously, CAR T-cell therapy works great in myeloma, but we still have not proved that it is a cure. The biggest challenge is finding a way to use [CAR T-cell therapy] and harness that power to cure our patients.

Articles

Larry Anderson, MD, PhD, discusses emerging therapies for patients with multiple myeloma that were highlighted at the 2019 ASH Annual Meeting.

CAR-T, Novel Combos Continue to Show Benefit in Multiple Myeloma

Longer follow-up of the ECHELON-1 trial solidified a benefit in progression-free survival (PFS) with the combination of brentuximab vedotin (Adcetris) and doxorubicin, vincristine, and dacarbazine (AVD) compared with AVD plus bleomycin (ABVD) in patients with Hodgkin lymphoma, explained Syed Rizvi, MD.

In the multicenter, open-label study, patients treated with brentuximab vedotin plus AVD (A+AVD) had a 31% reduction in the risk of disease progression or death versus ABVD, which was statistically significant, after a median follow-up of 48.4 months (HR, 0.69; 95% CI, 0.542-0.881).

 At 4 years, the PFS rate was 81.7% with the brentuximab vedotin regimen versus 75.1% with ABVD.

In March 2018, the FDA approved brentuximab vedotin for use in combination with chemotherapy as a frontline treatment for adult patients with stage III/IV classical Hodgkin lymphoma, based on earlier findings from the ECHELON-1 trial.

“The skepticism that we had is not as [prevalent] as it used to be. We are increasingly becoming open-minded to the idea [of A+AVD],” said Rizvi, an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center.

Now, investigators are evaluating brentuximab vedotin in combination with immunotherapy (NCT01716806), Rizvi said. Other treatments, such as CAR T-cell therapy and BTK inhibitors, are also being explored in this patient population, Rizvi added.

 State of the Science Summit™ on Hematologic Malignancies, Rizvi discussed recent therapeutic advances in advanced-stage Hodgkin lymphoma.

: What is the current standard-of-care treatment for patients with Hodgkin lymphoma?

: ABVD has been the standard of care [in advanced Hodgkin lymphoma] for almost 14 years. However, about 30% of patients do not respond to [treatment], and the PFS rate is not 100%. We are trying to identify who the nonresponders are early on so we can get them appropriate treatment. We also want to potentially identify therapies that can lead to better PFS and, hopefully, overall survival.

What practice-changing updates in Hodgkin lymphoma were presented at the 2019 ASH Annual Meeting?

There were [results from] the ECHELON-1 study; a lot of us were skeptical early on about the PFS data with just 2 years of follow-up. They presented data from 4 years of follow-up, and [A+AVD] still looks promising compared with ABVD. There were certainly better PFS rates reported for PET2-positive patients, so that is encouraging, too.

Certainly, [the regimen] has some complications, which are more commonly [in the form of] neutropenia and febrile neutropenia. The effects of neutropenia and peripheral neuropathy results were reported at the 4-year follow-up. Lung toxicity is certainly less with this regimen as well.

Could other combination strategies with brentuximab vedotin have potential?

Brentuximab vedotin has been out for 7 to 8 years now and was initially approved in the second-line setting. Since 2018 it has been used for upfront Hodgkin lymphoma treatment.

Brentuximab vedotin is being used in conjunction with checkpoint inhibition. That is an exciting study, and many of us are waiting for the results. We want to see how some of these high-risk patients would benefit [from this combination treatment] or [how they would] not.

For a patient with stage III/IV Hodgkin lymphoma, what factors do you take into consideration when determining their optimal treatment?

The age of the patient, their smoking history, the integrity of their lung tissue, whether they have a history of lung disease, and whether they have a history of neuropathy or a condition that predisposes them to neuropathy—those would be some of the [important factors].

ABVD was the standard [chemotherapy option] in North America, but over the past 2 years, with brentuximab vedotin being approved for up-front use, many of us are considering whether patients have [disorders, such as] lung involvement, up front. Otherwise, [patients who are] nonsmokers or have no history of cytopenia [are usually treated with] brentuximab vedotin plus AVD, and then [we omit] bleomycin altogether.

What other novel agents are moving through the pipeline in Hodgkin lymphoma?

Personally, I find checkpoint inhibitors in conjunction with brentuximab vedotin quite interesting. Some data [show that] BTK inhibitors [have] some activity in Hodgkin lymphoma, as well, [and investigators are also looking at] them in combination with some of these agents, such as checkpoint inhibitors.

Is there any rationale to explore CAR T-cell therapy in Hodgkin lymphoma?

That is being explored. CAR T-cell therapy is [an approach in which] a lot of our patients would benefit. We have had a few patients treated with CAR T-cell therapy in Houston, Texas and North Carolina who have done well posttreatment. That is certainly something that is in the pipeline and we are excited about that.

Bartlett NL, Straus DJ, Dlugosz-Danecka M, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma (cHL): 4-year update of the Echeleon-1 study. 

. 2019;134(suppl 1):4026. doi: 10.1182/blood-2019-124116.

Seattle Genetics and Takeda announce additional analyses of Adcetris (brentuximab vedotin) ECHELON-1 and ECHELON-2 phase 3 clinical trials at the 2019 ASH Annual Meeting [news release]: Bothell, WA, and Cambridge, MA, and Osaka, Japan. Seattle Genetics, Inc; December 9, 2019. bit.ly/2tXAswp. Accessed January 27, 2020.

Syed Rizvi, MD, discusses recent therapeutic advances in advanced-stage Hodgkin lymphoma.

Brentuximab Vedotin Leads Treatment Progress in Hodgkin Lymphoma

Optimal management of treatment-related dermatologic adverse events (AEs) in patients with melanoma is essential for proper care, according to Tracey Liebman, MD.

“For the patients who develop nonspecific rash, pruritus or itching, and psoriasis or dry skin, we first try to start with conservative measures, especially for those who have a mild disease,” said Liebman. “We use emollients, moisturizers, or topical steroids of varying potencies depending on the severity. Unfortunately, if some patients do have more of a severe disease, then we have to focus on how we manage and control their disease. [This may result in] using systemic steroids and, occasionally, some may even have to stop their medication in order for the AE to improve.”

 on Advanced Melanoma, Liebman, an assistant professor in the Ronald O. Perelman Department of Dermatology, NYU School of Medicine, NYU Langone Health, discussed the identification and management of treatment-related dermatologic AEs in patients with melanoma.

: What are some of the cutaneous AEs that are associated with checkpoint inhibitors? Do they differ between PD-1 and CTLA-4 inhibitors?

: CTLA-4 and PD-1 inhibitors have many similar AEs. PD-1 inhibitors, in particular. [are associated with] one type of rash called a lichenoid eruption, in which patients experience purple, itchy lesions on their body, and it can occur in the mouth, as well. They could also have mucosal lesions, and some patients can even develop a more severe mucositis.

The most common AEs that we see with PD-1/CTLA-4 inhibitors are nonspecific rash, itching, and dry skin. Most of those patients have a mild disease that can be controlled with conservative measures, such as emollients, moisturizers, and topical steroids, although some patients do have more of a severe skin involvement and may require stronger medication, including systemic steroids.

What should healthcare providers be aware of regarding the severity of AEs?

Dermatologists are the experts at managing skin. In any cases where oncologists are treating patients and feel uncomfortable with managing their skin, they can always refer their patient to a dermatologist. We enjoy treating these patients.

Should there be more communication between providers and their referrals?

Our institution has a good open-door policy, and we share a lot of patients [with oncologists]. The oncologists know when they should send a patient to dermatology or when they want a little bit more help with [management of] these AEs.

I know the oncologists have good literature and guidelines to help figure out when to send their patients to a dermatologist or how to manage their initial patients. A lot of patients who are [referred to me by] from oncologists have already been managed very nicely; they are doing a lot of the right things. We just tweak the management a bit after that.

 inhibitors? When do they typically present?

 inhibitors have a wide variety of AEs, but importantly, 

 inhibitors can lead to proliferation of hyperkeratotic lesions. Patients can develop benign lesions, such as warts, but they can also develop malignant lesions, such as cutaneous squamous carcinoma and keratoacanthoma; that is something to look out for. This usually happens early in the first couple of months. Patients can also develop changes in their melanocytic nevi in the first several months of treatment. Some patients can also develop a second primary melanoma (SPM), and this is usually a melanoma that does not harbor a 

For patients on these inhibitors, what are the risks of developing an SPM?

-mutated advanced melanoma, but when the 

 inhibitors are given to these patients it affects all of the cells in the body. The 

 wild-type cells are affected, as well. The theory on why you have proliferation of these lesions and new neoplasms is that the 

 wild-type cells, instead of shutting down the proliferation, have a paradoxical effect and cause increased growth of those cells.

What are the benefits of concomitant treatment with BRAF and MEK inhibitors?

BRAF and MEK inhibitors have their own AEs. When they are combined, you have a decrease in the cutaneous toxicity on both sides. [Actinic keratosis], change of nevus, and acneiform eruptions, decrease. Overall, they are often used together because they help to decrease the AEs.

Could you discuss the increased risk of developing additional primary melanomas? How can this issue be monitored?

I typically see any patient with a history of melanoma or advanced melanoma in my practice every 3 months for the first 2 years. After that, [the visits] decrease to every 6 months. The risk of an additional primary melanoma is usually highest within the first year or so. Patients with a history of melanoma also have a risk of developing an additional SPM. We closely monitor these patients and make sure they come for regular follow-ups.

How would you define the current state of digital surveillance?

Right now, there is a wide range and variety of digital surveillance. Patients who have many atypical nevi will undergo total body photography. They get pictures of their whole body and we monitor that over time, which helps us identify melanomas and decrease extra biopsies of normal moles.

Sometimes we also do dermoscopic monitoring through sequential digital dermoscopy imaging (SDDI), in which we take a dermoscopic close-up image of the lesion. Then, we [take another image] 3 months later for short-term monitoring; if any changes occur, that is when we have to do a biopsy. Often, that can help us diagnose melanoma at a very early stage.

Right now, we are developing these new tools and trying to figure out which ones are most helpful to us and [that we are] using them on the right patients. High-risk patients who have many moles and a history of melanoma are those who we tend to put under close surveillance; for them, we use more of these high-tech tools.

Tracey Liebman, MD, discusses the identification and management of treatment-related dermatologic AEs in patients with melanoma.

Treatment-Related Dermatologic AEs in Melanoma Require Careful Management

Novel treatments, including CAR T-cell therapy and bispecific T-cell engagers (BiTEs), have helped revolutionize the treatment of patients with acute lymphoblastic leukemia (ALL), but researchers continue to refine use of these modalities, according to Lloyd Damon, MD.

“A lot of new CAR T-cell data came out with regard to ALL—[data showing] good expansion of CAR T cells in patients with ALL…and having consistency of the CAR T cells because patients seem to do much better on persistent CAR T cells over time,” said Damon, clinical professor of medicine in the Department of Medicine, director of Hematologic Malignancies and Bone Marrow Transplant, and the Robert O. and Angela W. Johnson Endowed Chair in Hematopoietic Malignancies, UCSF Helen Diller Family Comprehensive Cancer Center. “The theme of CAR T cells is trying to go forward and make them more effective, safer, and more persistent over time.”

Additional questions remain with the importance of allogeneic stem cell transplant, the evolving role of chemotherapy, and also how to best utilize the CD19/CD3-directed BiTE blinatumomab (Blincyto) in this space, Damon explained.

 on Hematologic Malignancies, Damon discussed the evolution of the treatment paradigm in ALL.

: How would you define the current management of patients with ALL?

: The BLAST trial used blinatumomab, an anti-CD19/anti-CD3 BiTE, to treat minimal residual disease (MRD)—positive individuals with the intent to go on to transplant. The trial was successful; 78% of patients became MRD negative and the vast majority of them made it to allogeneic transplant. It looked like their outcomes were better, especially compared with those who did not achieve MRD negativity with blinatumomab.

 for MRD-positive disease and it is the first agent approved by the FDA for [this patient subgroup]. It is leading a new charge, or treatment, in hematologic malignancies.

At the 2019 ASH Annual Meeting, a lot of new CAR T-cell data came out with regard to ALL, but new constructs are needed to see if there are ways to reduce toxicity. [We may need to] seek different antigens on ALL cells to look for improvements, or they may have different costimulatory domains—traditionally it has been 4-1BB and CD28, but something else could possibly offer advantages.

The last question that [comes to mind] is, “If you do succeed in getting patients into remission with CAR T cells, should you add allogeneic transplant?” There are conflicting data on whether that is important or not, so that is something that must be resolved. Pediatric patients with ALL who go through an allogeneic transplant are rare. In adults, it is more common; adult patients are more willing to go in that direction. That is something that needs to be addressed with future research as well.

Where do you see this field moving? How will it look, overall, as we enter a new decade?

We have to keep in mind that in most hematologic malignancies, chemotherapy does not solve all problems. Immunotherapy is important and where we place it [to ensure] successful regimens are incorporating immunotherapy modules—such as blinatumomab, other BiTEs, or inotuzumab ozogamicin&mdash;within the backbone of chemotherapy. I do not think ALL will ever be completely effective at treating patients without chemotherapy. However, the addition, timing, and scheduling of [these immune-based regimens] is definitely the next wave [of treatment].

CAR T-cell therapy does not appear to be our answer, as we have a high response rate but a high relapse rate [with that approach]. Then, there is the role of allogeneic transplant after CAR T-cell therapy. This is really important in ALL, compared with other conditions, such as lymphoma or myeloma.

Is there anything else about the current state of ALL treatment that is important to highlight?

It is critical that you appropriately identify individuals in remission with ALL and that allogeneic transplant be thought of early on in the treatment course. In ALL, we do not get much in the way of a second chance [with our patients’ treatment]. It is important to apply your best therapies upfront; in the relapse setting, things are substantially worse compared with other hematologic malignancies.

The thing that I have not spoken about is a new entity in Philadelphia (Ph) chromosome—like mixed-phenotype ALL. We are now better understanding the biology of that, but these patients do relatively poorly compared with those without the Ph-like signature. What are we going to do about it? The pediatricians are ahead of us working on that, but targeted agents, such as ruxolitinib (Jakafi) or dasatinib (Sprycel), may help overall.

Lloyd Damon, MD, discusses the evolution of the treatment paradigm in acute lymphoblastic leukemia.

BiTEs, CAR T-Cell Therapy Enhance ALL Armamentarium, But Questions Remain

The chronic lymphocytic leukemia (CLL) paradigm has evolved significantly with the addition of combination strategies, more selective BTK inhibitors, and fixed-duration approaches. Therefore, the next question being asked in the field is how to choose among the various options for patients, explained Bita Fakhri, MD.

“The field of CLL is moving at a pace in which we no longer have to choose the lesser of 2 evils, so patients have very good options,” said Fakhri, an assistant professor of medicine at the University of California, San Francisco School of Medicine. “It is mutual decision-making [between myself and my patients].”

 State of Science Summit™ on Hematologic Malignancies, Fakhri discussed data from several recent trials in CLL and focused on other regimens moving through the pipeline.

: Could you discuss the current state of CLL treatment prior to data that were presented at the 2019 ASH Annual Meeting?

: In the upfront setting, 2 major landmark trials were presented at the 2018 ASH Annual Meeting. In one of them, in an older population, researchers compared the commonly used chemoimmunotherapy option of bendamustine and&#8239;rituximab (Rituxan) versus the BTK inhibitor&#8239;ibrutinib (Imbruvica) versus&#8239;ibrutinib combined with rituximab. Researchers saw that both&#8239;ibrutinib-containing arms beat the chemoimmunotherapy regimen and met their primary end point of progression-free survival (PFS).

Based on this study, single-agent ibrutinib or&#8239;ibrutinib plus&#8239;rituximab is the current standard of care for older patients with CLL. At the same time, another clinical trial of younger patients with CLL compared fludarabine,&#8239;cyclophosphamide, and&#8239;rituximab&#8239;(FCR) when compared with&#8239;ibrutinib plus&#8239;rituximab, [in which ibrutinib/rituximab showed superior PFS].

[In both of these studies], the&#8239;ibrutinib-containing regimens became the standard of care over traditional chemoimmunotherapy.

At the same time, [there were data from] the CLL14 trial, which [evaluated] a chemotherapy-free, [regimen: a fixed duration] of 6 cycles of&#8239;obinutuzumab&#8239;(Gazyva) with&#8239;venetoclax (Venclexta). These findings were compared with findings of the CLL11 trial, which combined&#8239;obinutuzumab and&#8239;chlorambucil; the results were outstanding. The 2-year PFS rate of obinutuzumab combined with&#8239;venetoclax was 88.2% compared with the 64.1% 2-year PFS rate observed with obinutuzumab&#8239; plus chlorambucil in the CLL11 trial.

Based on these trials, either&#8239;ibrutinib as a single agent, combined with a monoclonal antibody, or a time-limited, chemotherapy-free regimen of&#8239;venetoclax plus&#8239;obinutuzumab are current standard options in the up-front setting.

During the 2019 ASH Annual Meeting, data were presented from the ELEVATE-TN trial, which compared the more selective BTK inhibitor acalabrutinib&#8239;(Calquence), either alone or in combination, with obinutuzumab, and obinutuzumab&#8239;plus&#8239;chlorambucil. Both acalabrutinib-containing regimens [led to higher PFS rates compared with obinutuzumab/chlorambucil]. Specifically, the 2-year PFS rates were 93% for acalabrutinib/obinutuzumab, 87% with single-agent&#8239;acalabrutinib, and 47% in the&#8239;obinutuzumab/chlorambucil arm.

Based on these studies, we have 2 great BTK inhibitors that can be used in the up-front setting in patients with CLL. Additionally, we can recommend&#8239;obinutuzumab&#8239;plus 1 year of&#8239;venetoclax to our patients who have a new diagnosis of CLL.

What factors do you take into consideration when deciding on a regimen for patients?

We have the data with BTK inhibitors, and we also have obinutuzumab&#8239;and&#8239;venetoclax; these are really good agents. Ibrutinib&#8239;and&#8239;acalabrutinib are lifelong treatments, so I always tell patients that they will be on this medicine as long as they tolerate it well and their disease is responding [to the therapy]. On the other hand, with&#8239;venetoclax and&#8239;rituximab, these are time-limited regimens for 12 months. Therefore, if someone cannot wrap their head around the fact that they have to be on a lifelong treatment, then venetoclax/rituximab is a better option for them.

Also, you always have to take into account the safety profile. BTK inhibitors have a risk of&#8239;atrial fibrillation and&#8239;[cardiac events], so if someone is coming in with a history of&#8239;atrial fibrillation or they already have some cardiac risk factors, venetoclax with&#8239;rituximab is a better option for them. At the same time, venetoclax is also associated with&#8239;cytopenia. Then, if someone is going to be on a regimen for 12 months, and is constantly [dealing] with&#8239;cytopenia, that&#8239;can pose some challenges. Tumor lysis syndrome with&#8239;venetoclax and&#8239;rituximab [also] causes a lot of fear.

Both strategies have positives and negatives: lifelong treatments, longer follow-up data, and the adverse event of&#8239;atrial fibrillation. In the ELEVATE-TN trial, the risk of atrial&#8239;fibrillation was about 4%, but&#8239;acalabrutinib and&#8239;ibrutinib have not been compared with each other directly. With venetoclax and rituximab, cytopenia is always a risk; this  is something patients have to take into account.

What role does chemotherapy have in a space with several targeted therapies?

We are very fortunate that we are living in the United States. I was at the International Workshop for CLL in June 2019 and we tend to forget that many countries, unfortunately, do not have access to these targeted agents; this includes some South American, Eastern European, and African countries.

For patients who have access to targeted agents, we have robust phase III clinical trial data showing that targeted agents are better than some chemoimmunotherapy regimens, especially in those with high-risk features. These include 17p deletion, 11q deletion, and unmutated 

; patients [with these] are not going to do well with chemoimmunotherapy.

Even when we come up with guidelines, we have to ensure that they are universal and as inclusive as possible. Until we get to a point where everybody has access to targeted agents, I do not think chemoimmunotherapy is dead. However, for patients who have access to targeted agents, the frontline agents are BTK inhibitors and&#8239;venetoclax.&#8239;

[An example of] future directions and clinical trials is the CAPTIVATE trial, which combined&#8239;ibrutinib&#8239;with&#8239;venetoclax. This showed really good overall response rates, durable responses, and high minimal residual disease (MRD)—negative outcomes. The field is not ready to practice based on MRD yet, but future clinical trial designs should focus on [fixed-duration] options, because we know that financial toxicities&#8239; are associated with lifelong treatments.

What advances are being made in the relapsed setting?

In the relapsed setting,&#8239;PI3K inhibitors&#8239;are definitely an option; [a trial] compared duvelisib (Copiktra) with ofatumumab (Arzerra), which can be offered as a sterile option for patients with relapsed/refractory CLL. The other PI3K inhibitor that has been approved for patients with&#8239;relapsed/refractory CLL is idelalisib (Zydelig), and was evaluated in combination with&#8239;rituximab compared with&#8239;rituximab plus placebo. The results were outstanding.

The problem with&#8239;PI3K inhibitors is the toxicities. At 2 years, 40% of patients are not able to tolerate them, mostly because of autoimmune complications such as colitis, pneumonitis, and hepatitis. If we can move toward a place that we can use them in a time-limited fashion rather than continuing them until disease progression, we can create a better place for them as treatment options for our patients with CLL.

So many options are on the horizon. At the 2019 ASH Annual Meeting, LOXO-305 went live; investigators found a noncovalent BTK inhibitor with activity against the most common resistance mutations in patients who have had previous BTK inhibitor exposure.

Of course, in patients who we call “double-refractory,” meaning they failed both a BTK inhibitor and a BCL-2 inhibitor, other therapies are definitely an option. TheTRANSCEND CLL 004 study, which involves many patients who have been heavily pretreated, has enrolled patients with up to 12 prior lines of therapy. The follow-up is short, but it is a very promising treatment strategy. Hopefully [this approach] can replace an&#8239;allogeneic hematopoietic stem cell transplantation, which is very toxic. If we can get there by utilizing another cellular therapy approach, why not?

Is there anything else that you would like to highlight?

I definitely want to bring 2 amazing [ongoing] phase III clinical trials to everyone's attention. The&#8239; Alliance A041702 trial is enrolling patients older than 70 years who have a new diagnosis of untreated CLL, and randomizing them to receive &#8239;obinutuzumab plus &#8239;ibrutinib versus&#8239;obinutuzumab,&#8239;ibrutinib, and&#8239;venetoclax&#8239;in a time-limited fashion. It is an amazing study because it is focused on a time-limited approach with the help from MRD data. The ECOG-ACRIN EA9161 trial is evaluating the same regimens—&#8239;obinutuzumab plus&#8239;ibrutinib versus&#8239;obinutuzumab,&#8239;ibrutinib, and&#8239;venetoclax&mdash;in a patient population with untreated CLL who are younger than 70 years. I believe [these studies] are going to&#8239;read out pretty soon.&#8239;The ECOG-ACRIN trial&#8239;is a bit behind in enrollment, but if anyone has a patient with a new diagnosis of untreated CLL who wants to be on a clinical trial, both studies are going to be practice changing.

Bita Fakhri, MD, discusses data from several recent trials in chronic lymphocytic leukemia and focused on other regimens moving through the pipeline.

Advances Continue at Rapid Pace in CLL Paradigm

Kathleen Madden, FNP, MSN, AOCNP, APHN, APHN

Being able to quickly detect and properly manage adverse events (AEs) that arise in patients with melanoma who are receiving immunotherapy is key to improving their experience with treatment, explained Kathleen Madden, FNP, MSN, AOCNP, APHN.

“I would definitely advise other providers to be very familiar with the agents that they are administering to patients, and understand the nuances of each of those drugs,” said Madden, citing AEs that are dermatologic, hepatic, and endocrine related.

For example, in the phase III trial CheckMate-067 trial, patients with previously untreated stage III/IV advanced melanoma were randomized 1:1:1 to receive either the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), single-agent nivolumab, or ipilimumab monotherapy. The rates of grade 3/4 AEs were 59% with the combination, 23% with nivolumab alone, and 28% with ipilimumab alone.

 during the 2020 State of the Science Summit™ on Advanced Melanoma, Madden, a nurse practitioner at NYU Langone Health's Perlmutter Cancer Center, discussed optimal management of AEs associated with various therapies for patients with melanoma.

: What are the most common immune-related toxicities that occur in patients with melanoma?

: Some of the most common toxicities for immunotherapy tend to be dermatologic, gastrointestinal (GI), hepatic, endocrine, pulmonary, and renal related; the top 2 AEs tend to be dermatologic and GI-related. We do spend a lot of time treating these toxicities, especially since they are 2 of the most clinically detectable for patients—and they are the ones that have earlier onset with longer duration.

What are some factors you consider when using steroids to manage these AEs?

Steroid therapy is sometimes a bit of a “necessary evil” because the immunotherapy AEs can be inflammatory in nature; it is almost anything you can slap an “itis” or an “opathy” behind. We manage those when they are unresponsive to supportive measures, then we use steroids, so we try to use it conservatively.

First and foremost, we try to have patients educated in order to inform us when AEs do start. We [operate under the] “see something, say something” mentality right away and tell patients not to delay voicing their concerns; you cannot muscle through these treatments. Patients really have to report AEs because, at the beginning, they'll have a slow and steady onset, but AEs can pick up the pace very quickly, especially if they're receiving combination therapy.

The dosing will depend on the grading of the toxicity, and we grade that by the information that the patients give us. We do have Common Terminology Criteria guidelines that we adhere to. We usually try to taper patients off of drugs at a steady pace, depending on the level of toxicity, and we support them through that. Often, antacid therapy is important so [acid reflux] and secondary issues with ulcers [do not occur]. For patients who are on high doses for longer periods of time, we may consider adding in some other adjunctive therapies so they don't develop secondary infections.

What advice do you have for healthcare providers who are trying to educate patients on these AEs?

I would advise other providers to be very familiar with the agents that they are administering to patients. Specifically for our patients with melanoma, whether they are given CTLA-4 inhibitor and/or a PD-1 inhibitor, providers need to be familiar with the nuances of each of those drugs. While there is a lot of overlap with the AE profiles, there are some things that are a bit nuanced, such as PD-1 inhibitors.

PD-1 inhibitors can have more pulmonary toxicity and renal toxicity, but patients also tend to be on PD-1 inhibitors a little bit longer. CTLA-4 inhibitors, especially if given standard dosing or in combination, will be administered in a briefer period of time.

We know that GI toxicities tend to be more nuanced in CTLA-4 inhibitors and the combination can exacerbate those sort of AEs. Again, knowing the drugs, knowing the nuances, keeping current with new updates, and educating their patients about the AEs are important.

[Something helpful] is when you are with patients, you can run through the organ systems. I like to run them from head to toe, and while I'm doing that, I am m gathering information; however, patients are also secondarily gaining information on what we are looking for. There is an educational process happening there that is a shared opportunity.

Could you provide a few examples of how and when these AEs present?

When I am discussing dermatologic toxicities with patients, I try to let them know that while AEs can start at any point in time, there is a median time frame when they can develop—it is usually during the first few months of treatment&mdash;and what that might look like. Again, AEs start to present in a slow-and-steady form, and it is important to report that on onset of one. It can open up the conversation, and we can inform patients what to look for at that next time point.

The level of toxicity that the patient is experiencing will determine and guide what sort of management measures that we have. Starting off with [supportive measures, we have] over-the-counter lotions or antihistamines if there is itching or rash, and then advance into steroids if and as needed.

With GI toxicities, they can start as early as the first infusion, but they can continue to develop after the first few infusions. We talk [with the patients] about these toxicities and what to look for, changes in frequency and consistency of bowel movements, and being aware of that and not to dismiss anything—especially if it lasts for more than 12 to 24 hours. We advise patients to notify our office because sometimes the signs and symptoms can be a little bit subtle; perhaps the AE is something that they have dealt with in the past. However, they should not dismiss it because they are now on a new therapy.

These [immunotherapies] are really potent medications and even though most of our patients are responsible adults, they are capable of handling their bodies. They have had [many] years of managing their bodies, and now we are in partnership [with them on that] and we have to gain that confidence, collaborative relationship, and trust. This is important so that they know that they are not complaining, they are not bothering us, that they are reporting, and that we have asked them to do that. AEs can happen at any point in time and the sooner we hear about these toxicities, usually the faster that we can intervene and the less inconvenient they can be for patients, and the better we can keep them on track and on schedule with their therapies.

What laboratory tests are used for these different ordering systems?

[The standard] include comprehensive metabolic and liver functions, which is part of a comprehensive panel. We are looking at complete blood count with differential, and we are looking at thyroid functions as baseline; this is because the endocrine system can be sensitive to T-cell modulation.

These are all things included in the package inserts. Sometimes, we also have patients get some baseline hormone tests, such as adrenocorticotropic hormone and cortisol. This is especially the case if patients are going to be on treatment for a while. There are expanded tests, but we usually use an expansion of tests depending on if a toxicity occurs. We do pregnancy testing on patients who are of childbearing age before each treatment, because the therapies can be embryo-fetal toxic. If we suspect that someone has an upset stomach and it is a little bit vague and they have some GI issues, it may not be colitis; however, it could be pancreatitis. Utilizing specific tests for amylase and lipase and pancreas enzymes is an example of an expansion of tests that are outside of the standard.

Could you discuss the CheckMate-067 trial and the implications of the safety findings?

The trial looked at ipilimumab in combination with nivolumab, and compared it with ipilimumab and nivolumab each as single agents. It looked at toxicity profiles, progression-free survival, and overall survival.

The AE profiles had a very high-resolution rate. Dermatologic toxicity tended to take longer to resolve and that was noted with PD-1 monotherapy, but some of those patients were also on maintenance therapy or on a longer-term therapy as a monotherapy possibly after induction treatment. Also, endocrine-related AEs have a low resolution rate, but that is not surprising; if we have an organ that is interrupted or disrupted permanently as a result of the T-cell modulation and immunotherapy, we can add hormone supplementation to it. Then, we can support those patients and they can continue on therapy.

What is your take-home message to your colleagues?

My take-home message is to pay attention to what patients are saying. We need to be good listeners and good investigators, and we need to be astute to the things that we are hearing. There can be a lot of vague information that can come in and that can be a little bit non-specific, but that is the part where we dive in and use our differentials to question what something could or could not be.

We need to understand what the toxicity profiles look like and how symptoms present so that can help guide us with the leading questions for our patients. Then, we can call out what is and isn’t going on.

Listening to your patients forging those relationships, and being a cheer team for them and knowing that they do not have to muscle through these things alone is important. That this is a partnership and we are here as their guides and their safety.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. 

. 2019;381:1535-1546. doi: 10.1056/NEJMoa1910836.

Kathleen Madden, FNP, MSN, AOCNP, APHN, discusses optimal management of adverse events associated with various therapies for patients with melanoma.

Optimal AE Management Required With Immunotherapy in Melanoma

Treatment with luspatercept-aamt (Reblozyl) reduced the severity of anemia in patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts who require red blood cell (RBC) transfusions, according to findings from the phase III MEDALIST trial that have now been published in the 

Additionally, the benefit with luspatercept extended to patients with refractory disease or those who were unlikely to respond to or were intolerant of erythropoiesis-stimulating agents (ESAs).

The published findings showed that 38% of patients in the luspatercept group had RBC-transfusion independence (RBC-TI) for ≥8 weeks compared with 13% of those in the placebo group (

 <.001), meeting the primary endpoint of the study.

The key secondary endpoint of RBC-TI for ≥12 weeks was met by a higher percentage of patients in the luspatercept group than in the placebo group at 28% versus 8% for weeks 1 through 24, and 33% versus 12% for weeks 1 through 48 (

 <.001 for both). In an analysis that applied the International Working Group (IWG) 2018 criteria, 19% of luspatercept-treated patients compared with 4% of patients on placebo had RBC-TI for ≥16 weeks during weeks 1 through 24; these rates were 28% and 7%, respectively, during weeks 1 through 48.

The study met an additional secondary endpoint, which was hematologic improvement-erythroid (HI-E) for ≥8 weeks, as assessed by IWG 2006 criteria. In weeks 1 through 24, HI-E responses occurred in 53% of patients on luspatercept compared with 12% of those in the placebo group. Fifty-nine percent of patients treated with luspatercept had an HI-E response in weeks 1 through 48 versus 17% of patients on placebo. During the double-blind period, no significant changes in neutrophil or platelet counts were observed.

“It is truly an honor to see work that began in Acceleron laboratories more than a decade ago and advanced successfully through a collaboration with Bristol-Myers Squibb now highlighted in the 

,” Habib Dable, president and chief executive officer of Acceleron, the company co-developing luspatercept with Bristol-Myers Squibb, stated in a press release.

 “Publication of the MEDALIST trial results in a journal of such eminence will certainly help to raise awareness among physicians of a potential new therapeutic option for treating anemia in certain patients with MDS.”

In December 2019, the FDA’s Oncologic Drugs Advisory Committee (ODAC) scheduled a hearing to review a supplemental biologics license application (sBLA) for luspatercept as a treatment for this patient population. However, later that month, the FDA waived the ODAC review of the application.

 The agency’s action date for a final decision on the sBLA is April 4, 2020.

The double-blind, placebo-controlled, phase III MEDALIST trial included 229 patients who were categorized with International Prognostic Scoring System (IPSS)-Revised very low-, low-, or intermediate-risk MDS with ring sideroblasts and required RBC transfusions. Patients were randomized to receive luspatercept at a dose of 1.0 to 1.75 mg/kg (n = 153) or placebo (76) subcutaneously every 3 weeks.

The median age was 71 years (range, 26-95) and 63% of patients were male. 

 mutations were identified in 93% of patients in the luspatercept group and 86% of those on the placebo arm. Ninety-five percent of patients previously received ESAs and 48% had received prior iron chelation treatment. The data cutoff date was May 8, 2018.

Ninety percent (n = 52) of patients in the luspatercept group who had a response had their first response at the starting dose of 1.00 mg/kg, and 7% of patients responded after dose increases at 1.33 mg/kg (n = 2) and 1.75 mg/kg (n = 2).

RBC-TI for ≥8 weeks occurred in 80% of patients on luspatercept who received <4 units per 8 weeks, in 37% of those who received 4 to 6 units per 8 weeks, and in 9% of patients who received ≥6 units per 8 weeks. In the placebo group, these RBC-TI rates were 40%, 4%, and 3%, respectively.

Additionally, the authors noted that the RBC-TI rates with luspatercept at ≥8 weeks during weeks 1 to 24 were similar regardless of number of baseline mutations: 1 (36.4%), 2 (34.9%), 3 (42.4%), and 4 or 5 (33.3%).

Regarding safety, the most common adverse events (AEs) found in ≥10% of the luspatercept and placebo arms were fatigue (27% vs 13%), diarrhea (22% vs 9%), asthenia (20% vs 12%), nausea (20% vs 8%), dizziness (20% vs 5%), and back pain (19% vs 7%). Grade ≥3 AEs occurred in 42% and 45% of patients on luspatercept and placebo, respectively; the most common were fatigue (5% with luspatercept and 3% with placebo) and injury (5% and 3%, respectively). Thirty-one percent of patients on luspatercept and 30% of those on placebo experienced ≥1 serious AE.

Longer-term analyses from MEDALIST were presented at the 2019 ASH Annual Meeting.

 At a data cutoff date of July 1, 2019, results showed that the RBC-TI at ≥8 weeks was 47.7% with luspatercept and 15.8% with placebo (odds ratio [OR], 5.978; 95% CI, 2.840-12.581; 

 <.0001). At ≥6 units per 8 weeks, the RBC-TI was 21.2% with luspatercept and 6.1% with placebo (OR, 4.17; 95% CI, 0.89-19.60; 

 = .0547). In those who received 4 to 6 units per 8 weeks, the RBC-TI was 48.8% and 8.7% with luspatercept and placebo, respectively (OR, 10.00; 95% CI, 2.07-48.28; 

 = .0013). In patients who received <4 units per 8 weeks, the RBC-TI was 84.8% with luspatercept and 40.0% with placebo (OR, 8.36; 95% CI, 2.51-27.83; 

Additionally, the longer follow-up showed that of the 73 patients treated with luspatercept achieving RBC-TI ≥8 weeks during the entire treatment period, 69.9% had ≥2 separate response periods, 38.4% of patients had ≥3 separate response periods, and 20.5% had ≥4 separate response periods.

“Patients with lower-risk myelodysplastic syndromes with ring sideroblasts for whom erythropoiesis-stimulating agents are not effective or are not an option have limited treatment options available beyond continued transfusions,” the authors concluded in the NEJM article. “Luspatercept significantly reduced the transfusion burden in a substantial proportion of these patients and was associated with mainly low-grade toxic effects.”

Luspatercept is also being evaluated in the ongoing COMMANDS trial (NCT03682536), which is evaluating the efficacy and safety of luspatercept compared with epoetin alfa for the treatment of anemia due to IPSS-R very low-, low-, or intermediate-risk MDS in ESA-naïve patients who require RBC transfusions.

Luspatercept is currently approved for the treatment of anemia in adult patients with beta thalassemia who require regular RBC transfusions.

Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. 

. 2020;382(2):140-151. doi: 10.1056/NEJMoa1908892.

New England Journal of Medicine publishes results of pivotal phase 3 Reblozyl (luspatercept-aamt) MEDALIST Trial [news release]: Princeton, NJ and Cambridge, MA. Bristol-Myers Squibb. Published January 9, 2020. https://bit.ly/2sgGqrA. Accessed January 9, 2020.

Bristol-Myers Squibb and Acceleron Pharma provide update on FDA advisory committee for reblozyl (luspatercept-aamt) [news release]: Princeton, NJ and Cambridge, MA. Bristol-Myers Squibb. Published December 6, 2019. https://bit.ly/34SCgEh. Accessed December 6, 2019.

Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes [supplementary appendix]. 

Fenaux P, Mufti GJ, Buckstein R, et al. Assessment of longer-term efficacy and safety in the phase 3, randomized, double-blind, placebo-controlled medalist trial of luspatercept to treat anemia in patients (pts) with revised International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. 

. 2019;134(suppl_1):841. doi: 10.1182/blood-2019-123064.

Treatment with luspatercept-aamt reduced the severity of anemia in patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts who require red blood cell transfusions.

Brittany Cote