Zanubrutinib (Brukinsa) is now FDA approved for the treatment of adults with Waldenström Macroglobulinemia.

“We are delighted by today’s FDA approval for [zanubrutinib] in its second indication, offering a new treatment option with demonstrated efficacy and safety benefits for patients with Waldenström’s macroglobulinemia. As shown in the ASPEN trial [NCT03053440], [zanubrutinib] can improve treatment outcomes for these patients and potentially make a positive impact on their lives,” Jane Huang, MD, chief medical officer of Hematology at BeiGene, said in a press release.

The regulatory decision was primarily based on data from the multicenter, open-label, phase 3 ASPEN trial, which compared zanubrutinib with ibrutinib (Imbruvica) in patients with Waldenström macroglobulinemia.

 presented during the 2020 ASCO Virtual Scientific Program showed that the BTK inhibitor was associated with a higher complete response or very good partial response (CR+VGPR) rate of 28.4% vs 19.2% with ibrutinib (

 = .0921).2 However, this did not meet the primary study hypothesis, which was superiority with CR+VGPR in the zanubrutinib arm per an independent review committee.

Moreover, the best overall response rate per investigator assessment in the zanubrutinib and ibrutinib arms at the time of the August 2019 data cutoff, were 28.4% vs 17.2%, respectively (

 = .0437); at the time of the January 2020 data cutoff, these rates were 30.4% versus 18.2%, respectively (

In the trial, 201 patients with Waldenström macroglobulinemia and a 

 mutation were randomized 1:1 to receive either 160 mg of zanubrutinib twice daily (n = 102) or 420 mg of ibrutinib once daily (n = 99). Patients were stratified based on 

 vs missing) and how many previous therapies were received (0 vs 1 to 3 vs 3 or more). Another cohort of 28 patients who did not harbor 

 mutations were given 160 mg of zanubrutinib daily.

The primary objective of the trial was to compare the efficacy of zanubrutinib with ibrutinib. The primary end point was CR+VGPR rate in patients with activating mutations. Key secondary objectives included further comparing the efficacy, clinical benefit, and anti-lymphoma effects of zanubrutinib vs ibrutinib and to explore the safety and tolerability of the 2 agents. Exploratory objectives comprised characterization of the pharmacokinetics of zanubrutinib in this patient population and to compare quality of life by EORTC QLQ-C30 and EQ-5D.

One-third, or 33.3% of patients who received zanubrutinib were over 75 years compared with 22.2% of those given ibrutinib. Moreover, patients on the zanubrutinib arm had higher rates of anemia than those on the ibrutinib arm, at 65.7% vs 53.5%, respectively. Most patients across the treatment arms received 1 to 3 previous therapies.

Regarding safety, those who had zanubrutinib experienced lower rates of atrial fibrillation compared with ibrutinib (2.0% vs 15.3%, respectively), as well hypertension (10.9% vs 17.3%), major bleeding (5.9% vs 9.2%), grade 3 or higher toxicities (58.4% vs 63.3%), adverse effects resulting in treatment discontinuation (4.0% vs 9.2%), and toxicity-related death (1.0% vs 4.1%).

Although rates of grade 3 or higher infections were comparable between the investigational and control arms, at 17.8% and 19.4%, respectively, zanubrutinib proved to have a higher rate of neutropenia vs ibrutinib, at 29.7% vs 13.3%, respectively.

U.S. FDA Grants BRUKINSA® (zanubrutinib) approval in Waldenström’s Macroglobulinemia. News release. BeiGene. September 1, 2021. Accessed September 1, 2021. 

Tam CSL, Opat S, D’Sa S, et al. ASPEN: results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). 

. 2020;38(suppl 15):8007. doi:10.1200/JCO.2020.38.15_suppl.8007

This article was originally published on OncLive as “FDA Approves Zanubrutinib in Waldenström Macroglobulinemia”

Articles

FDA Green Lights Zanubrutinib for Adults with Waldenström Macroglobulinemia

Newly standardized grading criteria will help to regulate the management of CAR T-cell therapy­–related toxicities, like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which require early and persistent management. As more CAR T-cell therapy drug becomes FDA approved, the utilization of this grading system may become more vital, said David G. Maloney, MD, PhD, in a virtual presentation given during the 2021 Pan Pacific Lymphoma Conference.

“Real-world evidence suggests that we have improved toxicity management from the original clinical trials, probably because of early treatment and patient selection. Fortunately, most of these toxicities resolve, but product selection is associated with different rates of toxicity. It is important to consider this,” said Maloney, a professor in the Clinical Research Division and the Leonard and Norma Klorfine Endowed Chair for Clinical Research at Fred Hutchinson Cancer Research Center, medical director of Cellular Immunotherapy at Seattle Cancer Care Alliance, and a professor of medicine in the Division of Oncology at the University of Washington School of Medicine.

Currently, FDA approvals for CAR T-cell therapies exist in aggressive non-Hodgkin lymphoma (NHL) with tisagenlecleucel (Kymriah), axicabtagene ciloleucel (axi-cel; Yescarta), and lisocabtagene maraleucel (liso-cel; Breyanzi), mantle cell lymphoma with brexucabtagene autoleucel (Tecartus), follicular lymphoma with axi-cel, pediatric or adolescent/young adult acute lymphoblastic leukemia with tisagenlecleucel, and multiple myeloma with idecabtagene vicleucel (ide-cel; Abecma).

“Each of these products is associated with a somewhat unique toxicity profile and they have their own REMS [Risk Evaluation and Mitigation Strategy] programs with the FDA, which makes the management of these toxicities somewhat challenging,” Maloney said.

Regarding the CD19-directed CAR T-cell therapies approved for use in aggressive NHL, treatment-related toxicities consist of CD19-independent events, such as chemotherapy-related toxicities, infection, anaphylaxis, recombinant lentivirus, and transformation, and CD19-dependent events, such as CRS, ICANS, B-cell depletion/infection, and tumor lysis syndrome.

Although fever is the defining characteristic of CRS, other associated complications can include hypotension, capillary leak, coagulopathy, marrow dysfunction, multiorgan failure, hypoxia, and hemophagocytic lymphohistiocytosis–like syndrome. ICANS can comprise headache, speech disturbances, delirium, seizures, focal deficits, and cerebral edema.

“There is an overlap between CRS and neurologic toxicity. Patients with really low-grade CRS often don’t have neurotoxicity, whereas patients with very severe CRS can often have very severe neurologic toxicity,” Maloney said.

Although tisagenlecleucel, axi-cel, and liso-cel are relatively similar products, differences in co-stimulatory domains elicit some differences regarding the onset and speed of CRS and ICANS, Maloney explained. However, no randomized trials comparing the therapies have been conducted and the pivotal trials utilized different grading systems for toxicity.

To standardize grading, the American Society for Transplantation and Cellular Therapy (ASTCT) set forth consensus grading criteria for CRS and ICANS.2

Both CRS and ICANS are graded 1 through 4 and overall grade is determined by the worst parameter. Regarding CRS, all grades feature a fever of 38 degrees Celsius or higher. Grade 1 CRS is fever only, with grade 2 through 4 featuring increasing severity of hypotension and/or hypoxia.

“The CRS grade is largely determined by the supportive strategies that are necessary to treat and support the patients,” said Maloney.

ICANS grading is determined by Immune Effector Cell-Associated Encephalopathy (ICE) score, Cornell Assessment of Pediatric Delirium score, depressed level of consciousness, seizure, motor findings, and elevated intracranial pressure/cerebral edema.

Both grading systems indicate that resolution of CRS or ICANS occurs when signs attributing to grading are no longer apparent.

Notably, CRS and ICANS are almost always reversible, but ICANS typically presents later than CRS, Maloney explained. Additionally, CAR T-cell counts in the blood tend to follow a crescendo-decrescendo pattern.

As such, increased proliferation of CAR T cells through factors, such as tumor burden, antigen escape, more concentrated infusion of CAR T cells, and the addition of fludarabine to cyclophosphamide-based lymphodepleting chemotherapy, is associated with a greater pre-treatment risk of severe CRS and ICANS. Additionally, severe CRS can lead to CAR T-cell expansion.

“CAR T-cell proliferation and peak count are associated with both response and toxicity,” Maloney said. “Earlier intervention is often considered in patients with high pre-treatment risk and in frail patients with pre-existing comorbidities.”

Earlier intervention should also be considered for patients with high post-infusion risk, including those with early or rapid progression of clinical toxicity, because they are at risk of more severe CRS and ICANS.

As the field develops a greater understanding of CAR T-cell therapy, management strategies for CRS and ICANS are improving, although they still vary widely between institutional practices, Maloney said.

“The goal of treatment of CRS and ICANS is to control these severe acute toxicities and prevent persistent toxicities while waiting for resolution of CRS or ICANS, and to avoid impairment of anti-tumor activity,” Maloney said.

Ultimately, general management strategies for CRS and ICANS include admittance to an intensive care unit for any-grade toxicity, investigation/exclusion of other etiologies, monitoring of vitals, ICE score, daily labs, and imaging if indicated, use of supportive care, and integration of immune modulation therapies if needed.

Supportive care measures include cooling, acetaminophen, antibiotics, granulocyte colony–stimulating factor, transfusions, fluids, oxygen, seizure prophylaxis, vasopressors, airway protection, and ventilation. Immune modulation options that interrupt the cytokine cascade include tocilizumab (Actemra), which is FDA approved to treat CAR T-cell therapy­–induced severe or life-threatening CRS, as well as siltuximab (Sylvant) and anakinra (Kineret). Corticosteroids are also utilized for immune modulation.

“CRS is not the only cause of fever, and ICANS [is] not the only cause of encephalopathy in these patients. Always consider the differential diagnosis to avoid a disaster,” Maloney noted.

Additional considerations, such as risk before and after infusion, stability of CRS components, age, variations in clinical trial designs, differences in CAR T-cell constructs, and variations in institutional practices can influence one’s interpretation of the CRS management guidelines, Maloney added.

Prolonged cytopenias and hypogammaglobulinemia are also frequently seen with CAR T-cell therapy, Maloney said.

Prolonged cytopenia that last more than 30 days post-infusion is observed in more than 30% of patients across approved CAR T-cell therapies. Notably, cytopenias are more frequent and more severe in patients with high-grade CRS, and treatment options include transfusion support, autoimmune processes, and transplant in rare cases.

Hypogammaglobulinemia is an on-target toxicity that arises from the ongoing elimination of CD19 B cells so long as functional CAR T cells are present. Patients with low immunoglobulin G (IgG) at presentation are more likely to develop hypogammaglobulinemia, but a minority of patients with normal IgG at infusion will require ongoing intravenous immune globulin support, which is suggested for patients with IgG less than 400 mg/dL.

Notably, patients who receive CAR T-cell therapy require ongoing follow-up for second malignancies and potential genetic risks from therapy, concluded Maloney.

Maloney D. Management of CAR-T toxicities. Presented at: 2021 Pan Pacific Lymphoma Conference; August 9-13, 2021; Big Island, HI. https://bit.ly/3ABmu04.

Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. 

 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758

Newly standardized grading criteria will help to regulate the management of CAR T-cell therapy¬–related toxicities, like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

New Toxicity Grading Criteria Help Standardize Management of CAR T-Cell Therapy-Related AEs 

The number of FDA approved CAR T-cell therapies has increased from 3 to 5 drugs in the past year. This novel treatment regime shows promise to continue to evolve in the coming years, providing hope for patients with relapsed hematologic malignancies that failed to respond to prior chemotherapy treatments, says Kelly Garvin, BSN, RN, OCN.

In a recent interview with Oncology Nursing News®, Garvin, from the Department of Malignant Hematology, H. Lee Moffit Cancer Center, discussed her 

School of Nursing Oncology meeting. She outlined how nurses can 

 in detecting CAR T-related adverse events (AEs), and commented on how the evolution of CAR T-cell therapy has continued to change the prognosis for patients with blood cancer and where she hopes the treatment direction will go.

Oncology Nursing News: How can nurses anticipate, and respond aggressively to, CAR T-cell therapy-related AEs?

Good question. One thing that we do is we have specially trained nursing staff. So, the nurses that work on the CAR T-cell floor are almost intensivists. In other words, we can float nurses from the intensive care unit to the CAR T-cell floor, but we cannot load nurses from MedSurg to the CAR T[-cell therapy] floor. So, these nurses, first of all, have to be specially trained in how to recognize the signs and symptoms of cytokine release syndrome, neurotoxicity, and ICANS.

Another thing that we do is we take vital signs more often. So, instead of [taking vitals] once a shift, we do it every 4 hours. We can do a cranial nerve check every time we go in there. We can be on the lookout for signs like headaches, aphasia, or confusion. We can ask the patient to write out a sentence and notice if there's any tremors in their penmanship that might be indicative that something is brewing. We can take their temperature more often. We can use family members to help us and alert us if the patient seems a little off. So, things like that all work together to keep the patient safe.

Would you be able to comment on how CAR T-cell therapy has changed the outcomes and prognosis of patients with blood cancers?

Oh, this is my favorite thing to talk about. So much has happened recently. Last year, I gave this talk, and, at the time, there were only 3 products that were FDA approved for certain malignancies, and 1 of them had been approved days before I gave the talk. In fact, I had to redo all the slides just to include them. Now, there are 5 different products and there are more indications.

So, if I have a patient who, for example, [has] diffuse large B-cell lymphoma, 1 of the most common non-Hodgkin lymphomas diagnosed in the United States every year, and is very aggressive, [the] good news is that we can cure about two-thirds of these patients with traditional archtop chemotherapy and immunotherapy. But for the one-third who relapse, or don't respond, the data is not good. There's not much we can do. Standard of care says [to] try salvage chemotherapy and then take them to autologous stem cell transplant. But if chemotherapy didn't work that well the first time what's to say heavy duty chemotherapy is going to work the second time. Right now, there's a trial going on in my cancer center looking at whether CAR T-cell therapy is just as good or maybe even better than standard of care. So, for patients who maybe have poor prognosticating factors, like bad genetics, or maybe they have BCL2 or BCL6 translocation or overexpression, and it doesn't look like they're probably going to respond very well to chemotherapy, if we could take those patients, and identify them early and take them to CAR T-cell therapy, where we're not using chemotherapy to fight the disease, we're using the body and the patient's own immune system, might they have a better outcome? Might their remission be deeper and longer? That's what we're going for.

And what do you hope to see in the next 5 to 10 years?

So many good things. So, one of the hurdles that we have to get over with CAR T-cell therapy is that we're using the patient's own T cells, and we're sending them off to be manufactured and to be reprogrammed in a way that is better able to fight the cancer. But sometimes that process takes too long. These are patients who have seen multiple lines of therapy. By the time they get to CAR T-cell therapy, they might not be able to wait the 2, 4, or, in some cases, even 6 weeks to get those T cells manufactured for them. So, 1 thing that we're looking at is allogeneic T-cell therapy or off-the-shelf [therapy]. So, we'll have donor T cells, kind of like we have donor allogeneic stem cell transplant. So that's 1 area.

Another area is more indications. Can we use CAR T-cell therapy for other diseases? For example, follicular lymphoma, which often transforms into diffuse large B-cell [lymphoma], can we use it in follicular lymphoma, just like we can in diffuse large B-cell [lymphoma] to get better outcomes for these patients? As a matter of fact? Yes. Axicabtagene ciloleucel (Yescarta), the first generation CAR T-cell therapy, just became approved in that particular setting as well.

Another thing I'd like to see is maybe using CAR T-cell therapy as first[-line therapy] rather than in the relapsed/refractory setting. So, would it be better to maybe replace chemotherapy sometimes or replace stem cell transplant in some cases, and start with CAR T-cell therapy for some of these patients, especially if they have 

mutations, or other genetic markers that lead us to suspect maybe they're not going to respond very well to chemo? Let's start thinking: Can we use immunotherapy instead? That's what I'd like to see.

What is the grand takeaway for oncology nurses from your presentation?

Well, on a very tangible level, nurses who already do oncology and who see patients that have these B-cell malignancies, these multiple myelomas and these diffuse large B-cell [and[ follicular or mantle cell [lymphomas], they’re going to know how to prepare the patients that they've identified as good candidates for what CAR T-cell therapy will feel like and look like for the patient. So that's 1 thing.

And for the other nurses who maybe don't do lymphomas, I want to leave them with this idea: CAR T-cell therapy is huge. It's exciting. It's dynamic. And it's a very fun place to be in medicine right now. And stay tuned, more is coming down the pipeline.

Kelly Garvin, BSN, RN, OCN, discusses the impact of CAR T-cell therapy on patients and how nurses care for them, as well as her expectations on how indications will grow. 

CAR T-Cell Therapy Continues to Revolutionize Hematologic Cancer Treatment

Prescribing opioids for pain management, while traditionally a common defense against symptom burden, may not be appropriate for patients with certain blood cancers, according to Holly L. Geyser, MD.

Thanks to great advancements in the treatment landscape, survival rates have improved among many hematologic cancers. However, as a result, the risk of overdose, as well as the need to minimize risk of addiction, make other options potentially safer alternatives for certain patients.

Geyser, an addiction expert from the Department of Internal Medicine, Mayo Clinic, recently spoke with CURE®, a sister publication of Oncology Nursing News®, about her research in safely treating pain management in hematologic malignancies with opioid therapy.

Potential Consequences or Considerations in Opioid Management

Opioids are associated with some harsh consequences that require special consideration when prescribed, said Geyser. Some adverse events (AEs) like constipation, nausea, a little bit of confusion in some populations, and sedation are easier to manage and not so severe. However, opioids pose the risk of overdose, where either the breathing center or respiratory centers shut down, as well as the risk of addiction.

Patients at higher risk for addiction include those with preexisting chemicals dependencies to alcohol, tobacco, or other drugs of abuse. The usual age range of addiction is 18 years to 45 years, and researchers have observed that addiction is slightly more prevalent in males, said Geyser.

In addition, patients with psychological disorders, depression, anxiety, bipolar, schizophrenia, PTSD, history of personal sexual abuse, or trauma, all have an elevated risk of addiction and therefore require additional screening before being prescribed opioids for pain management. “This does not necessarily mean we should not give these patients opioids,” she explained, “It's just a warning sign that these people may need to be monitored more closely.”

Furthermore, literature has demonstrated that patients with cancer are also often at a higher risk for addiction than the average population.

When Are Opioids Considered Inappropriate?

Patients with hematologic cancers experience significant symptom burden, yet this population also often lives longer than the average 5-year prognosis that tends to be associated with patients with solid tumor cancers.

ASCO guidelines currently state that patients should be screened for pain at every encounter. For patients with complex needs, the inclusion of other health professionals should be considered. If patients have not responded to conservative pain management and report symptom burden that impairs function or causes distress, clinicians may prescribe a trial of opioids, monitoring closely for AEs. In addition, clinicians must be fluent in concepts such as tolerance, dependence, abuse, and addiction as they relate to opioids use, and should utilize universal precautions to mitigate abuse, addiction, and adverse consequences. 2

However, these ASCO guidelines, last updated in 2016, are geared towards a heterogeneous group of patients with cancer, and do not specify how to treat hematologic malignancies, Geyser explained.

She cited myeloproliferative neoplasms as an example of a cancer where patients can reach a normal life expectancy, but often report high symptom burden, “Oftentimes, opioids are first-line therapy for these people, [but] 20 years of that is going to buy you consequences.”

With patients whose treatment strategies allow them to live beyond their cancer, providers need to start asking the following questions:

Is it appropriate to continue these people on unregulated opioid use?

Could they develop secondary consequences from the opioid usage that will need to be addressed?

Could these consequences become potentially more harmful than the original cancer itself?

Unless the cancer is immediately life threatening, first-line approaches should be composed of non-pharmacologic therapy in conjunction with pharmacologic therapy, advised Geyser. Non-pharmacologic therapies can include physical and occupational therapy, as well as Tai Chi and acupuncture. Science has offered great evidence that these alternative therapies are effective at alleviating pain, particularly when they are offered alongside non-opioid drugs such as Tylenol and ibuprofen.

Other alternatives for patients whose mechanism of pain are unlikely to respond to opioids include gabapentin and interventional therapies that can target the nerves themselves. Placing analgesics and steroids into many joints or other spaces within the body can help provide significant relief without risk of addiction of overdose. These services are usually performed by pain management specialist, so Geyser recommends including these specialists as part of the team.

Opioid therapy becomes appropriate when the pain is moderate to severe, or when it appears to become symptomatic. Opioid therapy initiated at a low dose and slowly increased can be fairly safe so long as patients receive consistent monitoring.

Geyser explained that she participated in a study that assessed the number of conversations physicians held with their patients about opioid uses and concerns. They found that the percentage was very low, between 20% to 30%, respectively. The study indicated that physicians have very busy schedules and don’t often find the time to focus on these types of conversations. This is where the oncology nurse can truly have an impact.

Engaged nursing staff represent the first and frontline discussion points with patients. For this reason, Geyser strongly encourages nurses to be aware of the general guidelines surroundings opioid use for patients, correct dosages, etc., as well as how to monitor patients on prescribed opioids when they come into the office. Ask: “Are they extremely agitated? Are they angry, or discriminating, or displaying violent, or potentially violent behavior? Are they showing signs and symptoms of opioid [addiction]?”

Geyser concluded that “anything that might suggest taking a closer look at the whole situation is oftentimes done better by nursing staff, in my opinion, than physicians or first-line providers. They are the key to all of this.”

Geyer HL, Gazelka H, Mesa R. How I treat pain in hematologic malignancies safely with opioid therapy. Blood. 2020 Jun 25;135(26):2354-2364. doi: 10.1182/blood.2019003116. PMID: 32352512.

Paice, Judith A., et al. "Management of chronic pain in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline." 

. 2016;34(27): 3325-3345. DOI: 10.1200/JCO.2016.68.5206

As patients with hematologic cancers live for normal life expectancies, the consequences associated with opioid use becomes more severe. 

Minimizing Inappropriate Opioid Use in Patients with Blood Cancers

Tisagenlecleucel (Kymriah) has induced durable outcomes in treating adult patients with relapsed/refractory follicular lymphoma and is comparable to other available products in terms of safety, said Stephen J. Schuster, MD.

Tisagenlecleucel resulted in an objective response rate (ORR) of 86.2% at the median follow-up at 10.9 months, according to results from the phase 2 ELARA trial (NCT03568461), which were presented during the 2021 ASCO Annual Meeting. In total, 94 patients with relapsed/refractory follicular lymphoma were included in the trial, of whom 66.0% experienced a complete response rate.

The study has yet to determine median duration of response, as well as median time to next anti-lymphoma treatment. In addition, neither the median progression-free survival (PFS; 95% CI, 12.1–not evaluable [NE]) nor the median overall survival (OS; 95% CI, NE–NE) has been reached, however, the 6-month PFS was 76% (95% CI, 65%-84%) with the CAR T-cell therapy.

“These findings offer hope in the sense that if a patient needs therapy, and existing therapies are inadequate—if they go through a couple of therapies, such as anti-CD20–based therapies like rituximab [Rituxan] with or without chemotherapy, and it is not working—this is an alternative that will work in those situations where [those] therapies have failed,” said Schuster, director of the Lymphoma Program and lymphoma translational research at Penn Medicine, and Robert and Margarita Louis-Dreyfus Professor in chronic lymphocytic leukemia and lymphoma clinical care and research, in an interview with OncLive®, Oncology Nursing News®'’s sister publication.

“It offers hope even for the patients who do not need it, should they ever get into that situation. We already have 5 years of follow-up, and this study has just under 1 year of median follow-up, as of the last data cutoff, which was September 2020,” he added.

Schuster noted that throughout his experience treating lymphomas, or lymphoma-related blood cancers, follicular lymphoma—the second most common form of non-Hodgkin lymphoma—has presented itself as a particular challenge. There is a high volume of patients with follicular lymphoma, and while a large number of them are fine without therapy, or respond well to existing therapies, there remains a subset of patients with problematic disease or whose disease moves at a much faster pace than existing therapies can treat.

“We needed something new for them,” he said.

This study marked a new turning point in follicular lymphoma treatment because tisagenlecleucelis, a biologically-based treatment regimen, signified that even patients whose diseases have failed to respond or have demonstrated resistance mechanism to previous lines of chemotherapy, will still respond.

“Immunotherapies, like this form of cellular immunotherapy, are agnostic. All the things which bode for failure of response to conventional agents are irrelevant when we are using this approach,” he explained.

The research team had first piloted this approach in 2014, with a study that included 14 patients who required this type of advanced therapy. More than 5 years later, approximately two-thirds of those patients are still in remission.

In addition, the current advances in CAR T-cell approaches are crucial because much of the early CAR T-cell development was concerned with the associated adverse events (AEs) when treating leukemias versus lymphomas. Understanding which toxicities are associated with different malignancies are a crucial component in supporting patients undergoing CAR T-cell therapy, Schuster said. Even within a population of patients with lymphoma, the toxicities can vary greatly between patients with follicular and large cell lymphoma, he noted.

“There is a [misconception] that this is an incredibly toxic therapy, but it is not, [when we] look at the data,” Schuster concluded. “If we look at serious episodes of AEs that are unique to CAR T-cell therapy, for example, cytokine release syndrome [CRS], no grade 3 or higher CRS [was reported with the product]. In acute leukemias and large cell lymphomas, a significant percentage of patients, particularly in leukemia, will experience grade 3 or higher CRS. [This is] very exciting in that the safety signal is good.”

The toxicity associated with tisagenlecluecel has been reported to be minimal. The drug is therefore considered safe to be used in the outpatient setting.

Other similar therapies are also in the pipeline for this population. In early 2021, the FDA approved axicabtagene ciloleucel (axi-cel; Yescarta), another form of CAR T-cell therapy, to treat follicular lymphoma. Schuster acknowledged that the drug seems to be comparable in efficacy, although he suspects we do not currently have the same number of years of follow-up with that product. Axicabtagene is known to be a slightly more intense treatment and is associated with higher grade AEs. Both drugs seem to be equally active, he said.

A version of this article was published on OncLive as 

“Tisagenlecleucel Demonstrates High Rates of Durable Responses in Relapsed/Refractory Follicular Lymphoma”

Tisagenlecleucel is a CAR T-cell therapy approved to treat follicular lymphoma that has minimal toxicity and is safe in the outpatient setting.

Efficacy of Tisagenlecluecel Yields Viable Option in Treating Follicular Lymphoma 

A supplemental biologics application (sBLA) pursuing the approval of abatacept (Orencia) has been granted a priority review designation by the FDA.The drug is designed to prevent moderate to severe acute graft-versus-host disease (aGVHD) among patients that receive unrelated donor hematopoietic stem cell transplant and are of at least 6 years of age. 

The application is supported by data from the phase 2 ABA2 trial (NCT01743131), as well as a registry trial based on real-world evidence. Data from ABA2 showed that abatacept, when added to a standard GVHD prophylactic regimen given to patients with hematologic malignancies receiving a stem cell transplant from an unrelated, human leukocyte antigen (HLA)–matched or mismatched donor, led to a significant reduction in severe aGVHD and associated morbidity without increasing disease relapse.

Data from the real-world analysis proved to be consistent with those findings.

Under the Prescription Drug User Fee Act, the FDA will decide on the sBLA by December 23, 2021.

“While stem cell transplants are an effective treatment for aggressive leukemias and other hematologic malignancies, patients who receive stem cell transplants from unrelated and HLA-mismatched donors are at high risk for developing aGVHD,” lead study investigator Leslie Kean, MD, PhD, director of the Pediatric Stem Cell Transplantation Program at Boston Children’s Hospital and Dana-Farber Cancer Institute, stated in a press release. “There is a tremendous need to expand the stem cell donor pool by lowering the risk of aGVHD in both adults and children receiving unrelated donor stem cell transplants.”

The multicenter, phase 2 trial, was comprised of 2 cohorts: a single-arm cohort that enrolled patients receiving transplants from mismatched unrelated donors (MMUD; 7/8 cohort) and a randomized, double-blind, placebo-controlled cohort that enrolled patients receiving transplants from 8/8 matched unrelated donors (MUD; 8/8 cohort).

All participants were given a calcineurin inhibitor, either cyclosporin or tacrolimus, and dosing was initiated on day -2 and continued through at least day 100, as tolerated. Patients also received methotrexate on days 1, 3, 6, and 11; they underwent transplant on day 0. Participants given abatacept received the agent at a dose of 10 mg/kg on days -1, 5, 14, and 28.

The primary end point of the trial was cumulative incidence of severe grade 3/4 aGVHD at day +100, and a key secondary end point was severe aGVHD–free survival (SGFS) at day +180.2 Other end points comprised grade 3/4 aGVHD at day +180, grade 2-4 aGVHD at days +100 and +180, chronic GVHD at 1 year, non-relapse mortality, relapse, relapse-free survival, overall survival, cytomegalovirus reactivation and disease, Epstein-Barr virus reactivation and post-transplant lymphoproliferative disease, hematologic recovery, and donor engraftment.

In the 8/8 cohort, the 2 arms were balanced with respect to all parameters evaluated. The 7/8 was also noted to be well matched with Center for International Blood and Marrow Transplant Research (CIBMTR) calcineurin inhibitor/methotrexate controls for all variables except overall disease type. According to the investigators, the apparent mismatch in overall disease type resulted from a nonuniform case:control matching ratio for the abatacept cohort in that some patients who received the agent were matched 1:2 vs 1:3 or 1:4. Despite this imbalance, the analysis of time-dependent outcomes accounted for the matching-pair design and eliminated the effect of this imbalance on parameter estimation.

Results showed that in the 7/8 cohort, patients who received abatacept had a substantial decrease in the day +100 cumulative incidence of severe aGVHD. Those who received abatacept plus a calcineurin inhibitor/methotrexate, the incidence was 2.3% in the intent-to-treat population vs 30.2% in the calcineurin inhibitor/methotrexate CIBMTR controls (

Results from a post-hoc analysis demonstrated similarly superior outcomes in those in this cohort who received abatacept plus calcineurin inhibitor/methotrexate vs the CIBMTR controls who received calcineurin inhibitor/methotrexate plus anti-thymocyte globulin.

In the 8/8 cohort, a decrease in severe aGVHD was also observed with abatacept vs placebo, at 6.8% vs 14.8%, respectively (

= .13; HR, 0.45; 80% CI, 0.22-0.9). As the sample size for ABA2 was designed with an alpha error of 0.2, the cohort reached the protocol-specified statistical end point.

Notably, other end points were examined as exploratory analyses, and they all demonstrated significant improvement over the controls.

Additionally, in the 7/8 cohort, the SGFS rates with abatacept plus calcineurin inhibitor/methotrexate vs calcineurin inhibitor/methotrexate were 97.7% and 58.7%, respectively (

< .001; HR, 0.0). In the 8/8 cohort, these rates were 93.2% and 82.0% with abatacept vs placebo, respectively (

Regarding chronic GVHD, the abatacept regimen did not improve the condition. In the 7/8 and 8/8 cohorts, patients who received the agent experienced a 1-year mild-severe chronic GVHD cumulative incidence of 62.0% vs 51.9%, respectively, vs 45.9% and 45.3%, respectively, with CIBMTR and placebo controls (

= .55; HR, 1.17; 80% CI, 0.85-1.61, respectively).

Notably, the addition of abatacept to the regimen did not result in increased relapse in either the 7/8 cohort (HR, 0.45; 80% CI, 0.22-0.91; 

= .21) or the 8/8 cohort (HR, 0.86; 80% CI, 0.54-1.35; 

= .66). The relapse point estimate at 2 years in the 7/8 cohort for abatacept and the calcineurin inhibitor/methotrexate CIBMTR controls were 9.3% and 21.4%, respectively. In the 8/8 cohort, the 2-year relapse rates with abatacept vs placebo were 21.5% and 23.6%, respectively.

“For patients who receive unrelated donor stem cell transplants, in particular for racial and ethnic minority patient populations, there is a heightened risk of developing aGVHD, a potentially life-threatening medical complication for which there are no approved preventive therapies,” Mary Beth Harler, MD, head of Immunology and Fibrosis Development at Bristol Myers Squibb, stated in a press release. “We look forward to working with the the FDA to bring [abatacept] to this new population and employ pathbreaking science in an effort to address unmet needs of underserved patients.”

US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for Orenica (abatacept) for the prevention of acute graft versus host disease (aGvHD). News release. Bristol Myers Squibb. August 23, 2021. Accessed August 23, 2021. 

Watkins B, Qayed M, McCracken C, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. 

. 2021;39(17):1865-1877. doi:10.1200/JCO.20.01086

This article was originally published on OncLive as 

“FDA Grants Priority Review to Abatacept for Prevention of Acute GVHD”

The FDA’s priority review designation to abatacept may help to expand the stem cell donor pool by lowering acute graft-versus-host-disease risk in both children and adults, experts say. 

FDA Grants Abatacept Priority Review to Prevent Acute GVHD

Kelly L. Garvin, BSN, RN, OCN, H. Lee Moffit Cancer Center, discusses where she hopes to see the direction of 

chimeric antigen receptor (CAR) T-cell therapy

 go over the next 5 to 10 years, in an interview with Oncology Nursing News®. Garvin recently presented about 

managing CAR T-cell therapy-related adverse events (AEs)

Some of the CAR T-therapy applications that Garvin would like to see include expanded approvals to use the therapy to treat other diseases and other lymphomas, as well as to potentially have the therapy approved as an earlier treatment for patients with TP53 or other biomarkers that suggest they won’t respond well to chemotherapy. One other change Garvin hopes to see is a shortened wait time to get the manufactured T cells ready for the patients.

“Sometimes [the] process takes too long,” she said. “These are patients who have seen multiple lines of therapy. By the time they get to CAR T[-cell therapy], they may not be able to wait the 2, 4, or even 6 weeks it takes to get those T cells manufactured for them. So, one thing we’re looking at is allogeneic T-cell therapy, or off-the-shelf... so we’ll have doner T cells, kind of like how we have donor allogeneic stem cell transplants.”

Overall, Garvin wants nurses to take away the idea that “CAR T[-cell therapy] is huge, it’s exciting, its dynamic, and it’s a very fun place to be in medicine right now and [nurses should] stay tuned­. More is coming down the pipeline.”

Videos

Kelly L. Garvin, BSN, RN, OCN, discusses what changes she hopes to see in CAR T-Cell therapy treatment over the coming years. 

Expert Weighs in on Future of CAR T-Cell Therapy Treatment Directions

Oncology nurses should be mindful of the potency of CAR T-cell therapies and be prepared to appropriately manage symptoms to ensure that patients with cancer can remain on their treatment, according to a presenter at the 

Kelly Garvin, BSN, RN, OCN, Department of Malignant Hematology, H. Lee Moffit Cancer Center, outlined ways that nurses could talk to their patients about CAR T-cell therapy, as well as how to recognize the unique adverse events (AEs) associated with the treatment and 

how to be vigilant when looking for these AEs.

Explaining CAR T-cell Therapy to Patients

The word chimeric has mythological roots. It once referred to a creature with the body of a dragon, the head of a turtle, and the tail of a serpent, according to Garvin. It is also defined as a tissue containing two distinct populations. Understanding this etymology helps demystify the concept of CAR T-cell therapy for patients.

CAR T cells are T lymphocyte cells that have been “reprogrammed” to target the antigens on the surface of a cancer cell (such as CD19 or BCMA)The CAR T cells then proceed to attack the cancer cells as if they were an infection.

The first step, according to Garvin, is to identify who would be an appropriate candidate to receive CAR T-cell therapy. Vital organ testing needs to then be done on the candidate. The next step is to withdrawal the whole blood from the patient, separate the T cells, and then return the rest of the blood to the patients.

The T lymphocyte cells are then sent to a special lab which uses genetic engineering to make the CARs. The T cells are then infused with the CARs and then that infusion undergoes a rigorous testing process. Currently, there are 5 approved products on the market (tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel) and each of these has a different clinical testing process.

Finally, before the patient receives the CAR T cells, they receive a lymphodepleting combination of fludarabine and cyclophosphamide. This process, according to Garvin, helps reduce the presence of other lymphocytes so that the reinjected T cells have more space to grow. Garvin recommended nurses give those patients two days of rest between the lymphodepletion and the administration of the CAR T cells. The cells, once returned to the body, multiply, and remain to provide surveillance.

“Once those T cells come in contact with the bad cell, the result can be very dramatic. They become activated, they start looking for the cancer cells, they start killing the cancer cells, and so the result can be dramatic and explosive,” Garvin explained.

The two main AEs that are associated with the use of CAR T -cell therapies are cytokine release syndrome (CRS) and neurotoxic events such as immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is typically the first observed AE and appears within the first week after treatment. While CRS is a natural event, the T-cell stimulation accelerates it and results in a potentially lethal increase in inflammatory cytokines. This, in turn, can lead to fever, edema, hypotension and organ disfunction, explained Garvin.

The other common AE oncology nurses should be aware of, according to Garvin, is neurotoxicity. On average, neurotoxic events occur 4 days after treatment. It usually follows CRS although it can be concurrent. Neurotoxicity is often biphasic and is usually marked by symptoms such headaches, aphasia, seizure, tremor, confusion, decreased LOC, and a difficulty with words.

“I remember once asking a patient a question and she just looked at me with a blank stare in her eyes, she didn't really seem to understand what I was saying,” she recalled. “[This patient is] normally chatty. Now, she doesn’t know what I'm what I'm asking her.”

Nurses should also be aware of other common AEs associated with the use of CAR T-cell therapies including prolonged cytopenias, B-cell aplasia and hypogammaglobinemia and hemophagocytic lymphohistiocytosis/macrophage activation syndrome, Garvin noted.

One of the easiest things nurses can do to remain vigilant in looking for AEs, she explained, is to take vital signs every 4 hours.

One of the first signs of CRS is a high fever. If a patient begins to show signs of a temperature spike, Garvin said her team is immediately ready. Other signs that point to the potential presence of CRS include fever, chills, hypotension, tachycardia, and hypoxia. If a symptom appears, the team’s first response is to administer antifebrile medications, as well as two liters of nasal canula.

While CRS can be life-threatening, it can usually be managed through early intervention. Sometimes, patients who have received CAR T cells are briefly sent to the ICU if their hypotension becomes unmanageable. But they are usually able to return, she said.

If the CRS (grade 3 or 4) becomes too difficult to manage with the regular interventions, then Garvin said her team will usually try tocilizumab.

“Tocilizumab is the therapy for severe CRS,” she said. “I've seen it reverse patient symptoms within hours. It's really dramatic. And if that doesn't work, sometimes we will use steroids.”

Just as with CRS, early detection is also necessary to effectively manage neurotoxicity. Garvin suggested that oncology nurses asking patients some of the following questions every 4 hours:

In addition, nurses can ask their patients to perform the following tasks:

Stick their tongue out and wiggle it back and forth,

Lift their arms straight into the air or straight out in front of themself,

Identify an object such as a clock or button, or

Write a coherent sentence such as “blue is my favorite color.”

If a patient is unable to complete these tasks, the nurse should suspect that neurotoxicity is brewing and react by calling for a neuro consult, she explained. The next action, according to Garvin, is to respond with seizure precautions. She requires that patients take nothing by mouth, and she lowers the bed to the lowest threshold. In addition, she said they administer levetiracetam to their patients because their seizure threshold is lower. They then increase the dose if the patient has a preexisting seizure risk.

Although CAR T cell therapies are associated with some potent AEs, the treatment continues to offer patients whose disease has not responded to various lines of treatment hope, according to Garvin. In coming years, Garvin said she hopes to see many changes in the landscape of CAR T-cell treatment, including allogeneic CAR T products and the use of CAR T-cell therapy for other diseases.

Garvin KL. CAR-T Therapy Nursing Considerations; Patient Education & Toxicity Management. Presented at: 5th Annual School of Nursing Oncology Live, Interactive Webcast. August 6-August 7, 20201.

Although the use of CAR T-cell therapies are associated with potentially serious adverse events, the treatment provides patients whose disease has failed to respond to previous treatments with hope, according to Kelly Garvin, BSN, RN, OCN.

CAR T-Cell Therapy 101: What Oncology Nurses Should Know 

Oncology nurses need adequate training to be able to recognize the signs and symptoms of CAR T-cell therapy-related adverse events (AEs) to ensure their patients can remain on their treatment, according to Kelly L. Garvin, BSN, RN, OCN.

Garvin, of the H. Lee Moffitt Cancer Center, recently spoke with Oncology Nursing News® and offered insight into how nurses could proactively help their patients manage CAR T-cell therapy-related AEs. Garvin recently presented on the topic at the 5th Annual School of Nursing Oncology.

Nurses who support patients receiving CAR T-cell treatments, Garvin noted, are specially trained to operate similarly to intensivists, which means they can float between the intensive care floor and the CAR T floor, while nurses from Med-Surg cannot. In addition, nurses who work with patients receiving CAR T treatments need to be able to recognize the early signs of cytokine release syndrome (CRS), neurotoxicity, and ICANS, before the symptoms begin to progress.

Garvin also noted that nurses should take their patients’ vital signs more often and perform other tasks to be quickly alerted if a patient is experiencing CAR T-cell therapy-related AEs.

“So, instead of once-a-shift, we (take vital signs) every four hours and do a cranial nerve check every time we go in there. We can look for signs like headaches, aphasia, or confusion,” she said. “We can (also) ask the patient to write out a sentence and see if there are any tremors in their penmanship.”

Proper training can help oncology nurses act as intensivists and quickly identify if their patients are experiencing any CAR T-cell therapy-related adverse events. 



Oncology Nurses Who Proactively Manage CAR T-Cell Therapy-Related AEs Can Ensure Their Patients Remain on Treatment

Treatment with low-dose venetoclax monotherapy may be effective in reducing tumor activity in patients with heavily pretreated multiple myeloma or light chain (AL) amyloidosis harboring t(11;14), according to data recently published in the 

Across the study population (n = 25), 44% of patients (n = 11) experienced a partial response (PR) or higher following treatment with venetoclax. Specifically, 71% of patients with AL amyloidosis and 33% of those with multiple myeloma achieved a PR or greater.

The study was conducted to assess the safety and efficacy of single-agent venetoclax, as well as to determine the importance of molecular markers in predicting treatment response. Additionally, potential resistance mechanisms of patients with multiple myeloma harboring t(11;14) were evaluated.

“We believe this study is a significant step towards multiple myeloma treatment by providing ways for selection of the optimal treatment regimens, prognostic biomarker, [resistance] mechanism, and increased understanding of t(11;14) role in multiple myeloma pathogenesis,” Hareth Nahi, MD, senior physician of Karolinska Institutet in Sweden, and coinvestigators wrote in the paper.

The trial enrolled 18 patients who were diagnosed with relapsed multiple myeloma and 7 with relapsed AL amyloidosis, all of whom harbored t(11;14). All patients who enrolled received a 100-mg dose of daily venetoclax for the first 3 days, with an escalation of 100 mg every third day up to a maximum dose of 400 mg daily.

Of the 25 patients who enrolled, 20 had diagnostic bone marrow biopsies available. Among the patients with available biopsies, 8 relapse bone marrow biopsies were examined. RNA sequencing was performed on 37 samples from patients with newly diagnosed multiple myeloma, 10 of which harbored t(11;14).

Overall, 71% of patients with AL amyloidosis and 33% of those with heavily pretreated multiple myeloma achieved a partial response or greater after receiving treatment with low dose venetoclax. 

Hematology