Ashley Hay, BSN, RN

Immune receptor inducible co-stimulator (ICOS), essential to the regulation of T cells, is playing a trending role in innovative cancer immunotherapy research; early data of its potential advantages suggests continued investigation. Expressed by activated cytotoxic T cells and regulatory T cells, the ICOS molecule could potentially serve as an indicator of immune response to therapy and is being evaluated across multiple treatment strategies. Furthermore, the dual effect of the ICOS/ICOS-L (inducible co-stimulator ligand) axis may provide a potential opportunity to have said pathway targeted by both agonist and antagonist antibodies.

As a member of the CD28 superfamily, the ICOS pathway begins via ligation expressed on B-cells and phagocytes. A downstream pathway is then triggered, regulating both T-cell proliferation and secretion of cytokines. On activated CD4 and CD8 T-cell subsets ICOS is upregulated, possibly representing a sensitive and strategic quantifier in targeting responses for select diagnoses of patients with cancer.

Oncologist Julio C. Chavez, MD, MS, is the current principal investigator of multiple clinical trials related to the use of immunotherapy and targeted agents. Chavez, an associate member in the Lymphoma Section of the Department of Malignant Hematology at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, discussed the use of this emerging immunologic trend in the oncology setting, stating, “The ICOS is a novel immune checkpoint that is associated with T-cell development, specifically T follicular helper [Tfh] cells. It is thought that Tfh cells are important in oncogenesis, particularly in T-cell lymphomas; specifically in angioimmunoblastic T-cell lymphoma [AITL] and peripheral T-cell lymphomas [PTCL] follicular type.”

Developing modern strategies to predict and accurately monitor treatment response remains an important piece of the clinical management puzzle. While immunotherapy holds innovative potential in the oncology sector, current therapies offered may only benefit a small fraction of patients. And, though more conventional imaging modalities (such as CT and MRI) remain current standards of assessment, certain limitations of these exams exist along with potential lag time between imaging and response assessment. Hence, an increased interest in comprehensive research efforts to identify a helpful marker, specifically one that accurately reflects the patient’s response to immunotherapy. PD-L1 immunohistochemistry and T-cell repertoire sequencing have been utilized as biomarkers, predicting response to immunotherapy; however, these novel approaches do still require invasive site biopsies.

Results from Early Studies of ICOS Agents

Several clinical trials utilizing the ICOS checkpoint in treating both solid and liquid tumor cancers have already been conducted and early responses have been mixed for monotherapy agents. However, investigators still believe in the potential of this checkpoint as part of combination regimens.

NCI-9930 is a phase 1 study (NCT02520791) of the ICOS blockade by MEDI-570, an ICOS-directed human afucosylatedIgG1 kappa monoclonal antagonistic antibody, in patients with relapsed/refractory malignant T-cell lymphomas. A total of 5 dose levels were studied, with 12 cycles of intravenous administration of MEDI-570 given every 3 weeks. Promising clinical results were documented in certain subtypes of angioimmunoblastic T-cell lymphomas (AITL)—there were 4 partial responses and 7 cases of stable disease, and the agent also resulted in reductions in targeted ICOS-positive T lymphocytes. Also, MEDI-570 was found to be well tolerated among recipient patients.

Chavez commented on the MEDI-570 trial, saying, “This was a dose escalation/expansion phase 1 study that just completed enrollment. We presented the preliminary efficacy at the American Society of Hematology [ASH] meeting in December 2020. Patients enrolled in the study were heavily pretreated, including prior autologous transplantation. MEDI-570 proved to be safe. It was particularly efficacious in AITL with 4 out 12 partial responses, which were durable. Given its safety, I believe that MEDI-570 can be combined with other agents known to have activity in T-cell lymphomas, including chemotherapy.”

Chavez was asked to express his view of whether or not ICOS research trials should continue along with potential corresponding value and benefits within the oncology sector. He stated, “ICOS is a novel checkpoint that targets T cells [that] are involved in oncogenesis, particularly lymphomagenesis. Given the preliminary safety and efficacy of MEDI-570, it has the potential to be safely combined with other agents.” Chavez added, “Therefore, [utilizing ICOS offers] potential improvements in the treatment of T-cell lymphomas, which usually have a poor prognosis.”

Feladilimab (formerly GSK3359609), an ICOS receptor agonist non–T-cell depleting monoclonal antibody, was first studied in an open-label, multicenter, phase 1 trial (INDUCE-1; NCT02723955) in those with advanced solid tumors of varied histology. Safety, dose escalation, and expansion phases were explored with feladilimab as both a monotherapy and in combination with varied treatment options. Several study arms currently aim to investigate the use of feladilimab along with other therapies, including pembrolizumab (Keytruda) and a multitude of chemotherapies at standard-of-care doses and schedules (docetaxel, pemetrexed, paclitaxel, gemcitabine, or fluorouracil [5-FU]), in addition to dostarlimab (Jemperli), cobolimab, or bintrafusp alfa. The study is currently recruiting, with an estimated study completion date of December 2024.

Among 10 evaluable patients treated with feladilimab, 5-FU, and platinum chemotherapy with or without pembrolizumab from the trial, 2 patients had partial response and 6 had stable disease. In those not treated with pembrolizumab, 9 of 10 patients experienced at least 1 adverse event (AE). Three serious events were reported, 2 of which were potentially related to the study treatment. With the addition of pembrolizumab, 94.7% of patients experienced at least 1 AE, including 15 serious events, 11 of which were potentially treatment related. No grade 5 events were observed in either cohort.

In the urothelial carcinoma expansion cohorts, in patients who previously received a PD-1/PD-L1 inhibitor, feladilimab monotherapy induced an overall response rate (ORR) of 7%, a disease control rate for at least 18 weeks of 21%, and a duration of response of 6.1 months. The median overall survival (OS) was 14.5 months and 77% of patients were still alive at 6 months. With feladilimab in combination with pembrolizumab in patients naïve to PD-1/PD-L1 inhibition, the ORR was 22%, the disease control rate for at least 18 weeks was 44%, and the median duration of response was 8.3 months. The median OS was 10.7 months and 64% of patients were still alive at 6 months. Grade 3 or higher treatment-related AEs were reported in 9% of patients in the combination arm but none were observed in the monotherapy arm.

In the INDUCE-3 trial (NCT04128696), patients with PD-L1–positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) were enrolled in the double-blinded phase 2/3 study in which feladilimab was given in combination with either pembrolizumab or placebo. In the INDUCE-4 study (NCT04428333), feladilimab was evaluated in a comparison of 2 randomized combination strategies: feladilimab with pembrolizumab and 5-FU plus platinum-based chemotherapy or placebo with pembrolizumab and 5-FU. Similar to the INDUCE-3 trial, participants had recurrent or metastatic HNSCC. However, as of April 2021, GlaxoSmithKline plc (GSK) has halted enrollment in both the INDUCE-3 and the INDUCE-4 phase 2 studies, following a recommendation by the Independent Data Monitoring Committee.

 Specific details surrounding data and reasons for the stoppages were not made public.

Vopratelimab (formerly JTX-2011) trials began in late 2016 and it was the first agonist anti-ICOS antibody to be studied; however, initial data from the phase 1/2 trial (ICONIC; NCT02904226) were unsatisfactory with only 1 of 67 patients showing a partial response from monotherapy and 8 of 106 patients responding on combination vopratelimab and nivolumab (Opdivo).

An analysis of the trial, though, showed that there were higher response rates and survival rates among patients with ICOShigh CD4 T-cell emergence who were also more likely to have a higher RNA signature cutoff of immune cell infiltration and PD-L1 expression. Among patients with this higher RNA signature (n = 11), the ORR was 27.3% and the disease control rate was 54.5%. The median progression-free survival was 3.1 months and the rate at 6 months was 36.4%. The median OS was not reached. In patients with a lower RNA signature (n = 23), the ORR was 13.0% and the disease control rate was 43.5%. The median progression-free survival was 2.2 months and the rate at 6 months was 20.1%. The median OS was 20 months.

In 2019, Jounce Therapeutics began an open-label phase 2 trial (EMERGE; NCT03989362), in which a combination of vopratelimab and ipilimumab (Yervoy; a CTLA-4 inhibitor) was evaluated; subjects had a diagnosis of either advanced and/ or refractory non–small cell lung cancer (NSCLC) or urothelial cancer and were exposed to prior PD-1/PD-L1 inhibition.

Vopratelimab is an agonist monoclonal antibody thought to generate an anti-tumor response by binding to ICOS. This refined approach, combining an anti-ICOS with an anti–CTLA-4 treatment has the potential to increase overall efficiency.

However, the NSCLC group was not projected to meet the criteria for continued enrollment into the cohort. Thus, the developers decided the trial should not be expanded to patients with urothelial carcinoma. Instead, the phase 2 SELECT trial (NCT04549025) is enrolling and exploring the use of an investigational PD-1 inhibitor JTX-4014 with or without added vopratelimab in biomarker-selected patients with metastatic NSCLC following 1 prior platinum-containing treatment regimen who are naïve to PD-1/PD-L1 inhibition.

Safety, efficacy, and tolerability of KY1044 (human anti-ICOS antibody) as a monotherapy and in combination with atezolizumab (Tecentriq) is being tested in a phase 1/2 trial (NCT03829501), aimed at those diagnosed with advanced malignancies. Eligible patients included those who were ineligible for other therapies or for patients who had no beneficial treatments available to them.

Preliminary results from the trial showed that 5 patients achieved a response to the combination regimen, which included a complete response in 1 patient with triple-negative breast cancer and partial responses in 4 patients.

In order to improve clinical cancer management, harnessing potential immunotherapy strategies that increase opportunities for monitoring and prediction are essential. Therapies utilizing antibodies that target immune checkpoints continue to be part of the novel shift toward immunotherapy in oncologic care. Immune checkpoint inhibitors can exhibit a response for those with certain malignancies, such as NSCLC, renal, bladder, and head and neck cancers. Patients with resistance to immune checkpoint inhibitors, however, may benefit from newly combined therapeutic approaches.12 Thus, continued research and strategy involving the possible use of therapeutic antibodies as both a monotherapy and as a part of innovative combination therapies is of interest and of potential future benefit to the oncologic community. Although an increased understanding of whether inhibition of expression or blockage would provide the most favorable therapeutic outcomes for select cases, it remains clear that utilizing the ICOS/ICOS-L signal pathway only has the potential to improve the future of oncology care.

“I believe that the targeting of ICOS represents a novel immunotherapeutic approach,” Chavez said. “There should be a continuous effort to further explore this pathway.”

1. Amatore F, Gorvel L, and Olive D. Inducible co-stimulator (ICOS) as a potential therapeutic target for anti-cancer therapy. 

 2018;22(4):343-351. doi:10.1080/14728222.2018.1444753

2. Xaio Z, Mayer A, Nobashi TW, Gambhir SS. ICOS is an indicator of T-cell-meditated response to cancer immunotherapy. 

 2020;80(14):3023-3032. doi:10.1158/0008-5472.CAN-19-3265

3. Chavez JC, Foss FM, William BM, et al. A Phase I Study of Anti-ICOS Antibody MEDI-570 for Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Angioimmunoblastic T-Cell Lymphoma (AITL) (NCI-9930). 

Blood. 2020;136(suppl 1):5-6. doi:10.1182/blood-2020-136465

4. Massarelli E, Balmanoukian AS, Vieito M, et al. INDUCE-1: Report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors. 

 2020;38(suppl 15):6544. doi:10.1200/JCO.2020.38.15_suppl.6544

5. Balar AV, Moreno V, Angevin E, et al. Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs). 

 2021;39(suppl 15):4519. doi:10.1200/JCO.2021.39.15_suppl.4519=

6. GSK Provides Update on Feladilimab, an Investigational Inducible T Cell Co-Stimulatory (ICOS) Agonist. News release. GlaxoSmithKline. April 14, 2021. Accessed August 10, 2021. 

7. Butterfield L, Kaufman H, and Marincola FM (Eds.). 

Cancer Immunotherapy Principles and Practice.

 (2nd ed, p351). Society for Immunotherapy of Cancer.

8. Yap TA, Gainor JF, Burris HA, et al. Association of an RNA signature (RS) with emergence of ICOS hi CD4 T cells and efficacy outcomes for the ICOS agonist vopratelimab (vopra) and nivolumab (nivo) in patients (pts) on the ICONIC trial. 

9. Jounce Therapeutics Announces Update on Vopratelimab Program. News release. Jounce Therapeutics, Inc. November 2, 2020. Accessed August 10, 2021. https://bit.ly/3DIvu5S

10. Marinelli O, Nabissi M, Morelli MB, Torquati L, Amantini C, and Santoni G. (2018). ICOS-L as a Potential Therapeutic Target for Cancer Immunotherapy. 

 2018;19(11):1107-1113. doi:10.2174/1389203719666180608093913

11. Patel MR, Naing A, Burris HA, et al. A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies. 

 2021;39(suppl 15):2624. doi:10.1200/JCO.2021.39.15_suppl.2624

12. Sainson R, Thotakura AK, Kosmac M, et al. An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression. 

 2020;8(12):1568-1582. doi:10.1158/2326-6066.CIR-20-0034

Articles

Developing modern strategies to predict and accurately monitor treatment response remains an important piece of the clinical management puzzle.

Immune Checkpoint to Watch: ICOS

The medical community has has felt the far-reaching impacts of travel bans caused by the 2019 coronavirus disease (COVID-19). Yet, the unexpected shift in daily activity may prove to have some lasting positive changes that provide alternative networking opportunities by virtual platforms. By the end of March, restrictions on travel had effectively canceled, delayed, or altered the format of all 2020 medical conferences, affecting both national and international events. Major organizations such as the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology, for example, successfully converted their planned presentations to a virtual format.

For many providers, especially those in the oncology sector, these meetings often contribute greatly to their professional development. Pertinent educational content that allows society members to learn about significant clinical updates and best practices are coupled with opportunities to engage with mentors or even collaborate on potentially groundbreaking future research. Thus, networking among colleagues is a vital aspect of these meetings, regardless of experience level.

Hiatus for In-Person Networking Opportunities

The COVID-19 pandemic has brought about a currently interminable pause on in-person professional networking. However, virtually connecting face-to-face with others as a vital means of communication is more accepted than ever before, thanks to relatively recent advances in online platform technology.

In a Twitter poll, followers of @TargetedOnc indicated that the greatest impact of medical conferences shifting to a virtual platform is the effect on networking opportunities (FIGURE), a critical component of the in-person model.

A self-described early-career clinician, Ishwaria M. Subbiah, MD, MS, has felt the effects of the current model. Discussing the downfalls of virtual meetings and conferences, she indicated that those smaller, casual in-person events intended to promote networking, such as coffee breaks or time spent in early-career lounges, “are challenging to reproduce” in a virtual platform. She went on to say that the loss of these opportunities is especially profound for those who find it difficult to have an extroverted voice on the virtual platform.

Subbiah added that “loss of informal events is palpable and difficult to quantify.” She identified “the unidirectional flow of information” presented during large online meetings as “a fundamental flaw [of] the virtual platform.” Expressing several obstacles, both personal and professional, she explained that the challenges of listening to an online meeting with young children at home are not easy to overcome.

“The value of face-to-face contact should not be diminished. The virtual platform has its strengths but when we reflect on... this virtual existence, we really see the value of interacting face to face and in person…. We really do feel that loss and it’s hard to quantify that loss,” Subbiah said.

In the spirit of future planning, Subbiah, who is a medical oncologist and palliative care physician at The University of Texas MD Anderson Cancer Center in Houston, went on to say that it is critical to embrace elements of the virtual experience as much as possible. Although she understands that online participation in medical conferences can initially seem like an isolating experience, making “a concerted effort to engage in nontraditional ways” can prove fruitful for attendees. Subbiah said that a loss of informal networking events unmistakable, but valuable connection remains possible through programming that continues after the conference has ended, such as via webinars or quasi–task force groups.

She also mentioned her participation in multiple social media groups relevant to her practice, such as a hematology/oncology women physicians’ group that has recently planned programs that encourage increased participation through smaller group conversation. These types of activities provide more of an open invitation to all, regardless of experience.

Although difficulties arise surrounding virtual medical meetings, Subbiah was quick to add several positive takeaways. She explained that regardless of all the medical meetings on her calendar being cancelled or postponed from February 2020 on, she was able to attend these events via virtual format, with some even offering discounted or free registration rates for potential attendees.

On a more personal note, she stated, “[Shifting to] the virtual platform opened up the world. I have given 3 talks so far to different groups in India. My husband, who is also an oncologist, in 1 day gave talks in Vienna, Japan, and [Washington,] DC…and was home for dinner.”

Experienced medical oncologist, hematologist, and published author Cary Presant, MD, of City of Hope in West Covina, California, recognizes the significant educational benefits and importance of potential networking opportunities through attending medical meetings, especially for practitioners just beginning their benefit, “they have to make certain that the people creating the presentations are capable of responding to their concerns as they complete a particular session.” He went on to suggest strategies such as person-to-person phone calls and Zoom meetings with peers or mentors to fill the professional networking gaps caused by the distancing required throughout the pandemic.

A former ASCO director and past president of the Association of Community Cancer Centers, Presant expressed his pleasant surprise at the agility with which major organizations were able to maintain the flow of information related to scientific breakthroughs, regardless of challenges. “All of these various levels of face-to-face meetings have been eliminated during COVID-19. The impact on these different organizations has been surprising to me. I had thought initially that there would be fewer participants in virtual meetings and that has proven to be not the case. There has been increased participation [across several major organizations].”

In discussing the unexpected levels of attendance, he explained that online meetings may accommodate both provider time constraints and budgets, allowing physicians to attend such events without having to take time away from their practice or laboratory for expensive travel and lengthy meeting days. “This was an exciting advance––to be able to have more participants in the meetings and yet, at the same time, [be] offered a challenge in terms of how to preserve networking.”

Presant added, “Therefore, there is added responsibility and added onus on the [individual] who is participating in clinical care and [administration] within their organization. I think it is incumbent upon individuals who are working in oncology to remember to take time to have these additional networking opportunities and to reflect upon new ideas that are coming out.”

Subbiah shared a similar sentiment in the context of her clinical practice. “The exchange of scientific information is profoundly important in a field as rapidly evolving as oncology. The need for dialogue is in the fabric of our field,” she said.

The now widespread virtual conference format presents its fair share of challenges during these unprecedented times. On the other hand, the lack of necessary travel to medical meetings promotes inclusivity for those on a limited budget as well as those unable to take time away from work or family obligations. Meeting organizers and health care providers are now fully harnessing the power of technology and connectivity around the world, broadening the spectrum of likely attendees. Thus, meetings now have the potential to achieve greater diversity, providing an even more valuable clinical conversation than before.

“You can tell that the conversation online during these meetings [is among] an audience that is much broader than it has ever been,” Subbiah said. “And so, the hope is that these types of interactions can continue even after meetings become more in-person [again]. The accessibility [of] these large meetings has changed without a doubt— frankly, permanently—during these virtual times.”

Although lost in-person networking opportunities may initially give one a sense of isolation or suggest a decrease in available channels, Subbiah and Presant agreed that the opportunities to connect with peers and mentors remain, and encouraged clinicians to reach out to meeting presenters. To take full advantage of these benefits, individual participants should remain vigilant and be willing to employ creative strategies to ensure they receive them.

The COVID-19 pandemic has brought about a currently interminable pause on in-person professional networking.

New Networking Opportunities Emerge As Medical Meetings Move to Virtual Format

New guidelines from he American Society of Hematology (ASH) for treating newly diagnosed acute myeloid leukemia (AML) in older patients recommend intensive antileukemic therapies over more conservative approaches, such as less-intensive therapies or supportive care, when treatment is considered tolerable.

The guideline panel included physicians based in the United States and Canada who represented a variety of subspecialties including frailty, geriatric oncology, and patient-reported outcomes. In an interview with 

, primary guidelines author Mikkael A. Sekeres, MD, MS, said the panel selection process was sensitive to gender and geographic distribution and included 3 leaders of cooperative groups in the United States for leukemia, as well as one from the National Cancer Institute of Canada’s leukemia group.

“These are the first guidelines published by ASH for any hematological malignancy. They are unique in how rigorously developed they were, [as they were] based on stringent standards for guideline development,” said Sekeres, a professor in the Department of Medicine at Case Western Reserve University School of Medicine as well as medical director of the Clinical Trials Unit at Taussig Cancer Institute of Cleveland Clinic, both in Ohio.

In weighing multifactorial risks and benefits of initiating potential antileukemic therapy in patients with AML older than aged 65 years, decisions to pursue treatment may be influenced by the physician’s or patient’s reluctance to assume an aggressive treatment strategy. The health care system also may contribute to poor prognoses in this patient subset due to treatment reluctance, as more than half of patients in this AML subgroup received no therapy and were not provided equal access to allogenic transplant once achieving remission.1 Because survival rates for this vulnerable population remain historically low, data regarding best practices are limited.

Methods for Determining Recommendations The recommendations were developed through a systemic review of evidence using the McMaster University Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, allowing the panel to provide recommendations that vary in strength based on certainty of evidence available. “Strong” to “conditional” recommendations were based on investigator-assessed certainty of evidence available.

Patient data included in the review were from patients with newly diagnosed de novo, treatment-related, and secondary AML aged 55 years or older with receipt of less-intensive or intensive antileukemic therapy and treated as part of a clinical trial with 20 or more patients. Patient data from those with acute promyelocytic leukemia, myeloid neoplasms associated with Down syndrome, and studies in which more than 75% of the population did not meet criteria for inclusion were excluded from the review.

The data reviewed by the panel showed a limited number of randomized studies available for this population. Although a number of retrospective data studies were examined, Sekeres pointed out the potential for “high selection bias in [such] studies” due to factors like existing serious comorbidities, such as end-stage lung cancer. “We made recommendations at different levels based on the quality of supporting data, couching our recommendations in the quality of data that we had,” he said, adding that critical outcome factors such as caregiver burden, quality-of-life (QOL) impairment, functional status impairment, and severe toxicity also factored in to the panel’s decisions. The weight of these factors varied slightly with each clinical question. Sekeres said the panel tailored factors they considered relevant in managing an older adult with AML to each specific clinical question. Unfortunately, often due to poor health or functional status within this population, patients did not participate directly in providing this data.

Although the panel began with approximately 20 clinical questions, Sekeres said they narrowed down the guidelines to 6 key areas of consideration. Clinical questions were determined and prioritized by the panel and are shown below with corresponding recommendations.

With strong evidence based on moderate certainty provided by the clinical data, the panel recommends offering antileukemic therapy to patients over best supportive care whenever possible. The comparison of intensive therapy versus best supportive care suggests a hazard ratio for death of 0.36 (95% CI, 0.26-0.50) based on low quality of evidence.

“This recommendation may seem incredibly obvious, but when you examine the data in the United States, you realize that a lot of older adults with AML are told to ‘get their affairs in order’ and seek no treatment,” said Sekeres. “Let’s be clear at the very beginning. If someone wants treatment, you should treat them,” and this should be done in alignment with their overall QOL goals.

Level of evidence is of a lower certainty based on the data available, but the panel favors intensive therapy—but placed a conditional recommendation on this determination. A review suggested that intensive therapy may produce a lower risk of death versus the alternative (HR, 0.78; 95% CI, 0.69-0.89) and that the risk of death may be lower at 1 year with this strategy (risk ratio [RR], 0.93; 95% CI, 0.85-1.01).

 “The [limited available] studies support more intensive antileukemic therapy if it is consistent with the patient’s individual goals,” Sekeres said. “That involves the careful balance of potential benefit in terms of getting into remission and survival versus risks of dying.” The risks to QOL and of being hospitalized for the first 4 to 6 weeks of diagnosis also weigh heavily on the decision-making process.

Sekeres said certain patients who receive one therapy and achieve remission still need additional intervention. “[Remission] is not enough. You need to give more [treatment] or else the chances of long-term survival diminish,” he said. Moderate quality evidence supports consolidation therapy for lower mortality (RR, 0.96; 95% CI, 0.89-1.03), longer survival times by a median of 3 months, and longer time to recurrence by a median of 1 month versus no consolidation.

“We only know this through indirect evidence. Long-term survivors who are older always receive more than one course of chemotherapy, but there are no randomized trials stating that more...is better than just one course [of treatment] or that a certain number of courses is the ideal amount,” Sekeres said. As such, the panel suggests treating patients who are not candidates for allogeneic hematopoietic stem cell transplantation with at least 2 cycles of intensive antileukemic therapy based on low certainty of evidence.

Considering potential treatment planning factors such as age, comorbidities, and patient 

goals can sometimes lead to a third branch of decision-making for older patients, Sekeres said. For example, some patients with AML are under the initial impression that they likely have 2 options for treatment: intense chemotherapy or no treatment with supportive care only. Sekeres explained that less-intensive therapy is a third option to strongly consider when trying to align care with the patient’s goals and life experiences. “In the United States, this commonly includes hypomethylating agents azacitidine and decitabine.”

As such, recommendation 4 is divided into 2 subgroups focusing on less-intensive therapy options using hypomethylating agents. “There doesn’t seem to be one preference for one hypomethylating agent over another or over other low-dose approaches,” said Sekeres. “As our guidelines were breaking, we knew of some trials that were going to be published that looked at combination therapy versus monotherapy.”

In a phase 1/2 study (NCT02203773) reviewed by the ASH panel, azacitidine plus venetoclax (Venclexta) demonstrated a promising efficacy rate with a tolerable safety profile versus administrations of azacitidine alone. However, the patients in this positive study were subjected to required hospitalization to receive the combination therapy.

 “In this case, if you think back to where we started regarding patient goals, you are now mixing goals,” Sekeres said. “If a patient wants a less-intensive approach, they typically want out of the hospital and to be at home.”

As such, the official recommendation from the panel suggests the use of either a hypomethylating agent or low-dose cytarabine as monotherapy based on moderate certainty of evidence in patients who are not eligible for intensive regimens. The second part of the recommendation suggests favoring monotherapy over combination therapy. However, if the patient chooses to move forward with combination treatment, low-dose cytarabine plus glasdegib (Daurismo) or a hypomethylating agent plus venetoclax can be used based on randomized trial data.

A conditional recommendation based on a low level of certainty led to the panel suggesting continuous therapy versus a time-limited approach.

Sekeres said that although this recommendation had limited supporting evidence, the specific amount of time is somewhat irrelevant. “[Patients] should continue to receive [the 

treatment] as long as they are responding,” he said. “There is currently no study that stops this therapy at a certain point.”

The last recommendation is a favorite of Sekeres’ because “this is where we make the very clear statement that if a patient wants blood transfusions while on hospice, that person should be allowed to do so. We consider it to be supportive care and not heroic,” he said.

Sekeres also explained the importance of finding a less-intensive approach for patients who have concerns about the effects of intensive therapy but still desire treatment, perhaps because of an expressed wish to live long enough for an upcoming family celebration or other personal reasons. Concerns such as hospitalization time, tolerability, potential adverse effects, overall QOL, and functional status are all incredibly important factors to consider when deciding the best course of action. In some instances, it may be more important to focus on tolerability than overall survival in this fragile population.

The ASH guidelines “are not intended to serve or be construed as a standard of care,” said Sekeres, but they are intended to assist physicians and educate patients in making decisions about potential diagnostic and treatment alternatives.1 The data herein highlight an unmet need for continued advocacy and research.

Sekeres said his interest in this patient population and corresponding research focus began during his fellowship, where he felt that a set of guidelines were important to address this clinical question with evidence-based treatment support for newly diagnosed AML.

“This is an extremely vulnerable population for whom the treatment decision at the very beginning of diagnosis is far from straightforward,” Sekeres said. “My job is somewhat easy because my decision trees don’t have a lot of branches to them. However, it’s hard because the therapy we are giving has an appreciable mortality itself.”

To provide fellow treating physicians with a key takeaway, Sekeres advised, “Your most important job as a health care provider working with a patient who has leukemia is making sure you are helping that person identify what his or her goals are and then meeting those goals with the treatments that you are offering.”

1. Sekeres MA, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. 

. 2020;4(15):3528-3549. doi:10.1182/bloodadvances.2020001920

2. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. 

. 2018;19(2):216-228. doi:10.1016/S1470-2045(18)30010-X

New guidelines from he American Society of Hematology for treating newly diagnosed acute myeloid leukemia in older patients recommend intensive antileukemic therapies over more conservative approaches.

Ashley Hay, BSN, RN | Authors

Articles

Immune Checkpoint to Watch: ICOS

New Networking Opportunities Emerge As Medical Meetings Move to Virtual Format

New ASH Guidelines Highlight a Call to Action for Treatment of Older AML Patients