Collecting Real-World Data in Hematologic Malignancies, at Home and Abroad

Greater use of real-world data (RWD) in studying and treating hematologic malignancies promises to speed up the delivery of new therapies and create more tailored regimens for groups who have not been well represented in clinical trials, including Black patients who have multiple myeloma.

That’s the mission of 2 research initiatives that seek to collect and curate data in blood cancers and disorders, according to a group of experts who gathered for a symposium, “The Role of Real-World Data Collection in Hematologic Malignancies,” during the 2021 American Society of Hematology (ASH) Meeting & Exposition, held in Atlanta, Georgia, and online.

ASH president Martin S. Tallman, MD, of Memorial Sloan-Kettering Cancer Center in New York, convened the wide-ranging panel of both US and European speakers, who discussed efforts by the ASH Research Collaborative and its counterpart in Europe, the HARMONY Alliance.

Tallman opened with an overview of where RWD come from and who collects them. “RWD sources in the United States typically include electronic health records, insurance claims, patient registries, and digital health solutions such as mobile applications and devices,” he said.

The ASH collaborative and HARMONY Alliance, said Tallman, “are positioned to make major impact” in using these data sources in both research and regulated settings. He then introduced John Gribben, MD, DSc, of Barts Cancer Institute and the London School of Medicine, a past president of the European Hematology Association, who began his talk by explaining HARMONY’s structure and funding. HARMONY now has more than 97,000 patient records, including those in acute myeloid leukemia (AML), chronic lymphocytic leukemia (CML), multiple myeloma, and myelodysplastic syndromes. An additional program, HARMONY Plus, covers data from chronic myeloid leukemia and Hodgkin lymphoma. Gribben made clear that data for some diseases are more complete than for others, but collecting more and better data is part of the work that’s ahead.

“Clearly, the aim of the project is to speed up the development of more effective treatment, predictions of blood cancers, and the use of big data to develop more personalized treatment for blood cancer patients,” Gribben said. “So, building the big data platform has allowed for a better understanding of these diseases. Obviously, everyone in this room understands the need for and importance of looking at RWD sets in terms of being more representative of our patients.”

William A. Wood, MD, MPH, a bone marrow transplant specialist at the University of North Carolina at Chapel Hill, who serves as chair of the ASH Research Collaborative data hub oversight group, discussed expectations, challenges, and solutions to accelerate research. For starters, he said, “The goal of aggregating completed RCT [randomized clinical trial] data is different than the goal of aggregating consensus RWD.”

Unlike traditional RCT data, RWD are likely being collected for some other use. “Some concepts overlap, yet some are different,” Wood said. “We can use RWD, for example, in a continuous fashion to facilitate ongoing clinical practice improvement and indeed, our dual goals.”

Wood explained the challenges of bringing together disparate data sources and using natural language processing to make the different data sets work together. It takes working with many stakeholders to achieve both the stakeholders’ goals along with 2 primary research purposes, which are: (1) to accelerate research with different methods and analytical approaches, and (2) to “improve clinical practice done locally at the site level, and also across sites in a collaborative way, something that is unprecedented at this scale in hematology,” said Wood.

Wood was the lead author of a paper by the ASH Research Collaborative that was published during the meeting; it discusses the start of a dedicated website on multiple myeloma.

 Said Wood, “It is launching, and it is here.”

Guillermo Sanz, MD, PhD, of Valencia, Spain, the HARMONY Alliance cochair, sought to explain where HARMONY ranks in terms of key research items in the European agenda. “It would be considered the start project of the Big Data for Better Outcomes program of the Innovative Medicines Initiative,” he said, referring to the effort to link major databases across the continent to find cures and treatments for Alzheimer disease, other cancers, and cardiovascular disease.

 Public and private entities have equal voices in HARMONY’s governance, he said.

In the United States, the FDA has advanced the cause of real-world evidence in several ways, notably through a 2018 guidance directed by the 21st Century Cures Act, said hematologist Nicole J. Gormley, MD, who is the FDA’s division director for histological indices.

Gormley outlined some concepts to be weighed when using RWD:

Do the data represent what they are intended to represent?

Do the data contain relevant information on exposure covariates and outcomes of interest for the study hypothesis?

She noted that while the FDA “does not endorse one data source over another,” some may have limits, depending on the study question. An electronic health record (EHR), for example, was created to assist with clinical care. “The data are limited to information captured in the EHR within a particular system and may not represent the entire clinical picture,” Gormley said. Other confounders may need to be considered.

Factors such as trial design and population selection matter—but nothing matters more than drug sponsors engaging with the FDA upfront before they make plans to use RWD in a submission.

Jan Geissler, chair of LeukaNET and cofounder of CML Advocates, in Riemerling, Germany, spoke from the perspective of what patients can gain from the use of RWD. To begin, Geissler said, this shift could better capture who actually lives with certain blood cancers. “If you look at CML data, [the patients in] most of the studies have an average age of 46 [or] 47 years, but the average [age of] incidence of CML is 65 years. So, limited external validity of that [exists] in a real-world patient population.”

But Geissler sees real potential in the use of RWD in understanding patient preferences, in explaining “the difficult tradeoffs that patients have, the actual patient experiences on therapies with all the symptoms, and what [having these diseases] means in real life.” Data captured remotely with mobile devices would offer a rich resource for researchers and drug developers, he said.

“We want to capture patient reality—what it means to get these therapies and diagnostics, and, [also], all the new innovations out there in the real world with [a variety of] populations: the elderly, migrant communities, and [other] people who we actually don’t have on the studies,” Geissler said. “I think we all agree that [clinical and regulatory decisions] need to be based on the data.”

Patients and the public do have concerns about how data are used, Geissler said. While patients have a personal stake in participating in trials and sharing data, the general public doesn’t. In the overall population, only about one-third of people support sharing medical data. “They’re concerned about data being shared with third parties,” he said.

Tallman then shifted the discussion to the clinical angle, starting with Kenneth C. Anderson, MD, of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute. Anderson addressed clinical applications of the ASH Research Collaborative and discussed its priorities:

Aggregating data on minimal residual disease (MRD) in multiple myeloma to optimize patient care.

Collecting data from Black patients, to improve their access to novel agents in multiple myeloma.

Understanding the relationship between COVID-19 and multiple myeloma, so that the infection can be better managed in patients who have this blood cancer.

Anderson said that the great strides that have been made recently in multiple myeloma—more than a dozen new therapies, increased progression-free and overall survival—are all associated with MRD negativity. Now, he said, priority tasks are to inventory medical centers to know how often MRD is being used in clinical decision making, and to collect longitudinal MRD tests to develop meaningful long-term data. “We want to analyze the relationship of real-world MRD negativity with clinical outcomes, so that we can ultimately make informed use of MRD in multiple myeloma care,” he said.

Despite the advances in multiple myeloma, Black patients, compared with White patients, have not shared equally in the benefits. And it is known that monoclonal gammopathy of unknown significance—a precursor to myeloma—is more common in the Black population. RWD can help overcome current barriers to drug access and allow more Black patients to benefit, Anderson said. Finally, he pointed to results showing that myeloma patients don’t respond as well as others to COVID-19 vaccination, especially if they are receiving CD38- or BCMA-targeted treatments. Starting at 5 sites, “We will capture longitudinal myeloma data to create a new COVID module for diagnosis, treatment, vaccination, and outcome of COVID-19 infection. [Then we] will expand our effort to 10 to 15 sites. And we will, in fact, identify and address disparities that are present in this context as well.”

Mario Boccadoro, MD, of the hematology division at Cattedra Ematologia, Torino, Italy, discussed efforts to create a registry of RWD from medical centers across Italy. The aims, he said, are to describe: (1) the disease in clinical practices; (2) subgroups; (3) different sequences and time to events; and (4) “last, but not the least important, the patient-reported outcome.”

Early plans call for including 30 medical centers (beyond major academic centers) and 1900 patients. So far, 210 patients are enrolled.

The case for RWD collection in AML came from Laura C. Michaelis, MD, of the Medical College of Wisconsin in Milwaukee. Using RWD, she emphasized, will benefit patients and community providers by:

“helping us accelerate trials for rare variants of an already rare disease”;

“illuminating valid contemporary outcomes” and possibly answer questions “that may not be appropriate for RCTs”; and

“showing us where bias exists in the clinical trials that we already have out there and help us develop a more equitable system of delivering care.”

The challenge of rare variants is especially problematic in AML. This disease, Michaelis said, has only 14,000 US diagnoses a year, with both prognosis and outcome dependent on molecular mutations. One study that needed 700 patients for a rare variant took 4 years to complete enrollment, for example—and patients may balk if they know they could be in a control arm.

“These rare variants require lots of patients, and it increases the amount of time that we need to get an answer,” Michaelis said. “This also not only increases the time for patients, but it also puts a number of subjects on therapies in which the outcomes are already largely known. And it decreases the likelihood of patient participation in clinical trials when you put patients on control arms. And that’s sort of been published before. So how can we bypass that? Well, RWD can help us understand what would be happening on the control arm.”

Using RWD to study questions that would be inappropriate for a RCT is very useful, Michaelis said. These include “operational questions,” such as “Should we perform a 14-day bone marrow?”; pharmacological questions, such as “Does everybody need 28 days of BCL2 inhibitor?”; and laboratory questions in MRD, such as whether the quality of tests in local laboratories is the same as that of specialized laboratories.

Additionally, unraveling bias is overdue and necessary, especially when it’s known that many patients from minority groups cannot get into trials because of comorbidities. Michaelis pointed to a Cleveland Clinic analysis that used 100,082 patients from its own database who were not in clinical trials; 88% had a comorbidity. Notably, when their data were swapped into a trial protocol, the results were nearly the same.

“A database of RWD can increase efficiency in clinical trials, especially for some of the rare variants of AML. It can provide useful answers to questions that we won’t or aren’t likely to test in a randomized fashion,” Michaelis said.

Lars Bullinger, MD, of the University of Berlin, then presented some of the first results with AML from the HARMONY consortium: 20,289 cases from 14 groups have been collected, and more are in the process of being transferred into the database. He highlighted an abstract that was being presented the next day at ASH that showed how gender affected molecular AML subclasses.

 Models are being developed that can guide treatment decisions down to the patient level, he explained, and that’s just the beginning.

“We continue to collect RWD at unprecedented speed,” Bullinger said. “While I have shown you that we have a lot of transfer data sets…many more have been identified and people are willing to contribute to HARMONY. So, I’m looking forward to the next year. We will definitely create more reliable data and do many more meaningful analyses.”

Jesus Maria Hernández-Rivas, MD, PhD, the chair of HARMONY and HARMONY Plus, then offered closing remarks. “In recent years, we have seen, incredibly, almost unpredictable developments in the field of hematology. We’re getting to know our genome increasingly better every day, and how that has an impact in the development of hematological diseases. At hospitals, we produce a huge amount of data that must be used in the benefit of patients.”

Patients, Hernández-Rivas said, are demanding that their data be used to speed the development of new treatments, and new protocols and systems must be created to make this happen. “We need to open our minds to reach cooperation agreements that facilitate data sharing,” he exhorted. “Moreover, all these data must be harmonized…to facilitate the data analytics.”

Hernández-Rivas expressed optimism that the ASH Research Collaborative and the HARMONY Alliance could work through these issues. However, he noted, “the only way to produce results combining all these databases is having the data with the same structure.” 

Tallman MS. The role of real-world data collection in hematologic malignancy research; ASH Research Collaborative. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 12, 2021; Atlanta, GA. Special interest session. https://ash.confex.come/ash/2021/webprogram?paper154650.html

Wood WA, Marks P, Plovnick RM. ASH Research Collaborative: a real-world data infrastructure to support real-world evidence development and learning healthcare systems in hematology. 

BD4BO: big data for better outcomes. Innovative Medicines Initiative. Accessed December 22, 2021. 

https://www.imi.europa.eu/projects-results/project-factsheets/bd4bo

Matteuzzi T, Dall’Olio D, Sträng E, et al. Impact of gender on molecular AML subclasses—a HARMONY Alliance study. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3438. https://ash.confex.com/ash/2021/webprogram/Paper152215.html

Articles

A presentation at the 63rd American Society of Hematology (ASH) annual meeting explored the collection of real-world data.

ASH 2021 Recap: Real-World Evidence

Sub-Q Isatuximab Combo Offers Safety, Efficacy Profile Comparable With Phase 3 Results in IV Formulation

Results from a phase 1b study of subcutaneous (sub-Q) isatuximab, used along with pomalidomide and dexamethasone, produced safety and efficacy results consistent with those seen in the phase 3 study that led to FDA approval of intravenous (IV) isatuximab with this combination to treat relapsed and refractory multiple myeloma (RRMM) in patients who have received at least 2 prior therapies.

The findings were presented during the 2021 American Society of Hematology Meeting & Exposition, held in Atlanta, Georgia, and online.

Isatuximab, sold as Sarclisa, was approved in March 2020 to treat certain patients with RRMM based on results of the ICARIA-MM study (NCT02990338), which found that isatuximab added to pomalidomide (Pomalyst) and dexamethasone demonstrated significant progression-free survival (PFS) of 11.53 months compared with 6.47 months with pomalidomide and dexamethasone alone (HR, 0.596; 95% CI, 0.44-0.81; 

This triplet combination also demonstrated an improved overall response rate (ORR) compared with pomalidomide and dexamethasone: 60.4% vs 35.3% (

Pharmacists have heralded sub-Q drug delivery in multiple myeloma as more convenient for patients and more efficient for hospital administrators; the arrival of sub-Q delivery for isatuximab gives this anti-CD38 therapy a feature achieved by a competitor, daratumumab (Darzalex).

The multicenter, open-label study presented at ASH 2021 evaluated the safety, pharmacokinetics (PKs), and efficacy of sub-Q vs IV isatuximab and pomalidomide in patients with RRMM who had received at least 2 prior treatments, including lenalidomide and a protease inhibitor.

Patients were randomized 2:1 to receive sub-Q 1000-mg isatuximab or IV 10-mg/kg isatuximab. Following evaluation of the safety, PKs, and CD38-receptor occupancy of isatuximab in the sub-Q formulation, new patients were randomized in 2 new cohorts to receive sub-Q 1400 mg or IV 10 mg/kg. Both formulations were administered once weekly for 4 weeks (cycle 1) and then every 2 weeks in combination with pomalidomide.

Primary end points assessed safety, including dose-limiting toxicity, injection-site reactions, and PK parameters. Secondary end points included ORR, PFS, CD38 receptor occupancy, and patient-reported outcomes.

Of the 34 patients randomized and treated, 12 received IV isatuximab 10 mg/kg with pomalidomide; 12, isatuximab sub-Q 1000 mg with pomalidomide; and 10, isatuximab sub-Q 1400 with pomalidomide. As of March 31, 2021, 7 patients (58%) from the IV group, 14 (33%) from the sub-Q 1000-mg group, and 7 from the sub-Q 1400-mg group remained on treatment.

The median time from the initial multiple myeloma diagnosis to the first study treatment was approximately 5 years; average number of prior lines of therapy was 3.5, with a range of 2 to 7 in the IV cohort, 2 to 6 in the sub-Q 1000-mg cohort, and 1 to 4 in the sub-Q 1400-mg group. When patients entered this study, the International Staging System classified them as 58.4%, 33.3%, and 60.0%, respectively. Due to time of accrual, follow-up was longer with the IV patients.

 Infusion reactions were infrequent, with less than 10% across all groups, and all grade 2 and at the first infusion. Local tolerability of the sub-Q infusion was very good, with a single instance of grade 2 site reaction of erythema and pain. There were similar instances of grade 3 or higher treatment-emergent adverse events and neutropenia across all groups and no treatment-related events that led to death or premature discontinuation. There was 1 case of neutropenia in the sub-Q 1000-mg group and 1 case of pulmonary infection in the sub-Q 1400-mg group. No maximum tolerated dose was identified.

 At 8 months, PFS was 73% in the IV and sub-Q 1000-mg groups and 89% in the sub-Q 1400-mg group. ORR, very good partial, and complete response rates were 66.7%, 33%, and 16.7%, respectively, in the IV group; 66.7%, 41.7%, and 25% in the sub-Q 1000-mg group; and 80%, 40%, and 20% in the sub-Q 1400-mg groups.

The authors concluded that sub-Q isatuximab and pomalidomide administration “appears to be a promising and convenient option for patients with RRMM.” 

Moreau P, Parmar G, Prince M, et al. A multi-center, phase 1b study to assess the safety, pharmacokinetics, and efficacy of subcutaneous isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2744. Accessed December 15, 2021. 

https://ash.confex.com/ash/2021/webprogram/Paper147136.html

Sanofi: FDA approves Sarclisa (isatixumab-irfc) for patients with relapsed refractory multiple myeloma. News release. Sanofi. March 2, 2020. Accessed December 15, 2021. 

Underscore Teclistamab’s Efficacy in RRMM

the MajesTEC-1 phase 1/2 study on teclistamab show that the treatment resulted in an overall response rate (ORR) of 62% (95% CI, 53.7%-69.8%) among patients with relapsed/refractory multiple myeloma (RRMM), suggesting that treatment responses were durable and deepened over time. These additional findings were presented at the 2021 American Society of Hematology Annual Meeting & Exposition.

Teclistamab is a T-cell–redirecting, bispecific immunoglobulin G4 antibody that targets the B-cell maturation antigen (BCMA) and CD3 receptors to induce T-cell–mediated cytotoxicity of BCMA-expressing myeloma cells, researchers explained.

The off-the-shelf therapy is manufactured by Janssen and received a Breakthrough Therapy Designation from the FDA in June 2021. Results of prior preclinical studies revealed that teclistamab killed myeloma cell lines and bone-marrow–derived myeloma cells.

The ORR was reported after a median follow-up of nearly 8 months in 150 patients who received the recommended subcutaneous (SC) phase 2 dose (RP2D) of 1.5 mg/kg across the phase 1 and 2 studies. All participants had received at least 3 prior lines of therapy and were triple-class exposed.

In the phase 1 study, the researchers sought to identify the SC RP2D and to characterize the treatment’s safety and tolerability; phase 2 was carried out to determine efficacy at RP2D.

Among responders, the median time to first confirmed response was 1.2 months (range, 0.2-5.5), while the ORR was consistent independent of cytogenetic risk or extent of prior therapy refractoriness.

However, median duration of response was not reached at the clinical cutoff; at this time, 92 of 93 responders were alive and continuing treatment. Median overall survival was also not reached.

58% of patients receiving teclistamab achieved a very good partial response or better

29% achieved a complete response (CR)
or better

By intent to treat, 25% of patients achieved minimal residual disease (MRD) negativity at a threshold of 10–5 (95% CI, 18.0%-32.4%)

In patients who achieved a CR or better, the MRD negativity rate was 42%

Progression-free survival rate at 9 months was 59% (95% CI, 48.8%-67.0%)

Throughout the course of the trial, no patients required a dose reduction and the most commonly reported adverse events (AEs) were cytokine release syndrome (CRS; 72%), injection-site erythema (26%), and fatigue (25%). One patient discontinued use due to adenoviral pneumonia. All CRS events were low grade, with the exception of one grade 3 event, and all resolved without treatment discontinuation.

Neutropenia, anemia, and thrombocytopenia were the most common hematologic AEs reported, while 5 patients developed immune effector cell–associated neurotoxicity syndrome.

A phase 3 study is currently underway, in part to evaluate the treatment in earlier-line settings and in combination with other agents. Additional data regarding patients with prior BCMA will also be reported. 

Moreau P, Usmani SZ, Garfall AL, et al. Updated results from MajesTEC-1: phase 1/2 study of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in relapsed/refractory multiple myeloma. Presented at: 63rd American Society of Hematology Annual Meeting & Exposition; December 13, 2021; Atlanta, GA. Abstract 896. https://ash.confex.com/ash/2021/webprogram/Paper147915.html

iStopMM: Investigators From Iceland Report First Results of Population-Based Screening for Multiple Myeloma

multiple myeloma (MM) develops, clinicians can detect precursor conditions, including monoclonal gammopathy of undetermined significance (MGUS), or related lymphoproliferative disorders (LPs). If patients receive a diagnosis at this stage, the chances of survival are greatly improved, but less than 5% of cases are caught at this point.

Five years ago, investigators in Iceland led by Sigurdur Kristinsson, MD, PhD, professor of hematology at the University of Iceland in Reykjavik, sought to evaluate what would happen if screening for MGUS were widely available: Would it lead to an improvement in overall survival?

They launched the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study (NCT03327597), described as “the first population-based screening study for MGUS that includes a randomized clinical trial of follow-up and treatment strategies.”

Early results from iStopMM were presented in 4 abstracts during the 2021 American Society of Hematology Meeting & Exposition, held in Atlanta, Georgia, and online.

In a video prepared for the International Myeloma Foundation, Kristinsson outlined the scope and mission of the project. “No one has ever done anything like this before—ever,” he said.

 Public support for and participation in the project have been tremendous, according to Kristinsson: “The president of Iceland was the first to give informed consent.”

The project is gathering next-generation sequencing (NGS) data on all those screened, which will be invaluable in researching biomarkers for MM and possibly other blood cancers. Another important aspect of the trial, Kristinsson explained, involves tracking participants’ quality-of-life scores; thus far, it appears that having a positive screen for MGUS does not detract from quality of life.

Although early results are “encouraging” and show that following patients with detected MGUS closely does yield more positive diagnoses, investigators are cautious. “Until final results of the iStopMM study become available, including data on survival and quality of life, we advise against systematic MGUS screening in healthy individuals,” they wrote.

According to the study authors, iStopMM was open to all Iceland residents born before 1976. Of the 148,708 eligible residents, just over half (54.3%; 80,759) provided consent for screening, and serum samples were collected over a 4-year period through the end of 2020. Investigators collected samples from 75,422 people (93.4%) who provided their initial consent.

Samples were tested for M proteins and free light chains; those with a prior diagnosis of MGUS were excluded. Per protocol and informed consent, those found to have MGUS were randomized to 3 study arms. Arm 1’s 1164 participants were not contacted, arm 2’s 1159 participants were followed based on current guidelines, and arm 3’s 1164 participants will be given intensive diagnostic and monitoring. Those who progress will receive early treatment.

Of the participants screened, 3725 (4.9%) were found to have MGUS over the course of the study. The condition was more likely to be seen as participants grew older: 2.3% among those aged 40 to 59 years; 6.2%, 60 to 79 years; 12.9%, 80 to 103 years. MGUS prevalence was higher in men than women (5.9% vs 4.1%). Most participants were low risk (38%) or low to intermediate risk (36%); 26% had high-intermediate risk, and high-risk MGUS was seen in just 0.2% of cases (9 participants).

After a median follow-up of 3 years, 194 patients received a diagnosis of LP: 9 in arm 1, 92 in arm 2, and 133 in arm 3 (

 < .001). In arm 1, 2 patients had smoldering Waldenström macroglobulinemia (SWM), 2 had WM, 1 had chronic lymphocytic leukemia (CLL), and 4 had MM.

Arm 2 included 1 patient with amyloidosis; 18, SWM; 2, WM; 2, CLL; 1, non-Hodgkin lymphoma (NHL); 56, smoldering MM; and 12, MM. Arm 3 had 2 patients with amyloidosis; 22, SWM; 5, CLL; 6, NHL; 82, SMM; and 16, MM.

In a separate abstract, the investigators found that they “did not find MGUS to be associated with SARS-CoV-2 susceptibility or COVID-19 severity. This is contrary to MM, which is preceded by MGUS.” The findings, they wrote, suggest that the immunosuppression in MGUS is different from that in MM, which has important implications for management and treatment.

Screening for monoclonal gammopathy of undetermined significance: a population-based randomized clinical trial. first results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 156. 

https://ash.confex.com/ash/2021/webprogram/Paper152333.html

iStopMM. International Myeloma Foundation. June 21, 2021. Accessed December 18, 2021. https://www.myeloma.org/black-swan-research-initiative/istopmm

Monoclonal gammopathy of undetermined significance and COVID-19: results from the population-based Iceland Screens, Treats, or Prevents Multiple Myeloma Study (iStopMM). Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Abstract 154. 

https://ash.confex.com/ash/2021/webprogram/Paper153145.html

The 63rd American Society of Hematology (ASH) Annual Meeting and Exposition featured leading experts who discussed research on multiple myeloma.

ASH 2021 Recap: Multiple Myeloma

ZUMA-7: Axi-Cel in Second Line Is the “New Standard” in R/R LBCL, Locke Says

Coming into the 2021 American Society of Hematology (ASH) Meeting & Exposition, Gilead Sciences had already announced that axicabtagene ciloleucel (axi-cel), sold as Yescarta, offered an event-free survival (EFS) rate more than 60% higher than that of the current second-line standard of care (SOC) for patients whose initial treatment for large B-cell lymphoma (LBCL) failed or whose cancer returned within a year.

For Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa, the lead study author of the phase 3 ZUMA-7 trial that studied the use of axi-cel in these patients,

The answer is clear, he said. Axi-cel, with years of data behind it, will quickly become the new SOC for these patients.

“ZUMA-7 met its primary EFS end point, demonstrating statistically significant and clinically meaningful improvement in efficacy with axi-cel vs second-line SOC in relapsed/refractory [R/R] LBCL,” Locke said during the ASH plenary session. “Results from the ZUMA-7 trial herald a paradigm shift: Axi-cel should be a new standard for patients with second-line R/R LBCL.”

Locke presented the data for ZUMA-7 to a large crowd, many of whom had heard the main data points but had other questions—for instance, if patients treated with axi-cel in the second-line setting fail, what happens next? Could autologous stem cell transplant (ASCT), which has been the second-line SOC treatment, now follow axi-cel?

“We don’t know what the appropriate therapy would be for a patient in the third line if they receive CAR [chimeric antigen receptor] T-cell therapy in the second line,” Locke said during a press briefing held prior to the plenary session. “We don’t understand [whether] the resistance mechanisms overlap….I think that will be an area of intense study in the years to come.” He said that in ZUMA-7, patients could go on to transplant if they progressed after receiving axi-cel; 19 patients did so, and 9 are still alive.

And in response to a question, Locke acknowledged that minority patients had been underrepresented in ZUMA-7; across the conference, there were discussions of how to make these expensive therapies available to all patients, regardless of socioeconomic status.

Axi-cel reached the market in the fall of 2017, within months of the approval of the first CAR T-cell therapy, and it is now approved for several types of R/R LBCL.

 Clinicians have become much better at managing the most significant adverse events (AEs) arising from cytokine release syndrome (CRS), which occurs as the customized therapy attacks the cancer within the patient’s body.

ZUMA-7 has an important difference from TRANSFORM, which studied lisocabtagene maraleucel (liso-cel) in LBCL

: Patients in ZUMA-7 were given corticosteroids only, not chemotherapy, prior to axi-cel treatment. “By giving CAR T-cell therapy as an earlier line of treatment, we are able to reduce the amount of chemotherapy patients are exposed to and get them quickly to a definitive therapy that can eradicate lymphoma for many years, if not forever, without a stem cell transplant,” Locke said.

But, some oncologists wondered, will bridging therapy be given in a real-world setting?

™ that this may occur, but the point of ZUMA-7 is that axi-cel can be manufactured quickly and patients can avoid added chemotherapy, which appears to have contributed to the study’s positive findings (see Clinical Spotlight, 

As City of Hope’s Alex F. Herrera, MD, noted in his plenary introduction, the question of using CAR T-cell therapy generally and axi-cel specifically arose quickly after clinicians saw its success in the third-line setting.

Locke noted that ZUMA-7 produced an advantage that is also seen with TRANSFORM: When the SOC for second-line R/R LBCL is salvage chemotherapy followed by a high-dose therapy and ASCT, the challenge is getting patients to the point of receiving the transplant in the first place. In ZUMA-7, 94% of those randomized to receive axi-cel were infused with treatment, while only 36% in the SOC group received a transplant.

Results from ZUMA-7 showed the following:

After a median follow-up of 24.9 months, the median EFS was 8.3 months (95% CI, 4.5-15.8) for patients treated with axi-cel compared with 2.0 months (95% CI, 1.6-2.8) for those who received SOC (HR, 0.398; 95% CI, 0.308-0.514; 

The objective response rate was 83% for axi-cel vs 50% for SOC (odds ratio, 5.31; 95% CI, 3.1-8.9; 

Median overall survival, evaluated as a preplanned interim analysis, favored axi-cel over SOC but did not yet meet statistical significance (not reached vs 35.1 months; HR, 0.730; 

= .027). Although the study did not include a crossover design, patients who failed on SOC and later received axi-cel could be confounding these results, Locke said.

Grade 3 or higher neurologic events occurred in 21% of the axi-cel group and 1% of the SOC group; common symptoms included tremor (26% vs 1%), confusional state (24% vs 2%), and aphasia (21% vs 0%). All were treated with corticosteroids. Median time to onset was 7 days with axi-cel and 23 days with SOC; median duration was 9 days vs 23 days.

Grade 3 or higher CRS was seen in 6% of axi-cel patients; CRS was managed with tocilizumab (65%), corticosteroids (24%), and vasopressors (6%).

Other grade 3 or higher AEs occurred in 91% of the axi-cel group vs 83% of the SOC group. Most common were neutropenia (69% vs 41%), anemia (30% vs 39%), and leukopenia (29% vs 22%).

The axi-cel arm had 1 treatment-related death; the SOC group had 2.

Axi-cel was superior to SOC across key subgroups, including those younger and older than 65 years, patients whose first-line therapy failed, and those whose relapsed within the first year after their first therapy succeeded.

A separate abstract presented during the ASH meeting found that patients in ZUMA-7 who received axi-cel reported superior quality-of-life outcomes than those who received SOC.5 “The superior clinical outcomes and patient experience with axi-cel over SOC should help inform treatment choices in second-line R/R LBCL,” the authors wrote.

Kite announces Yescarta CAR T-cell therapy improved event-free survival by 60% over chemotherapy plus stem cell transplant in second-line relapsed or refractory large B-cell lymphoma. News release. Kite/Gilead; June 28, 2021. Accessed December 14, 2021. 

Locke FL, Miklos DB, Jacobson C, et al. Primary analysis of ZUMA-7: a phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standard-of-care therapy in patients with relapsed/refractory large B-cell lymphoma. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2. 

https://ash.confex.com/ash/2021/webprogram/Paper148039.html

U.S. FDA approves Yescarta for relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. News release. Kite/Gilead; March 5, 2021. Accessed December 14, 2021. 

Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen reception (CAR) T cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pts) with relapsed or refractory (R/R) large B-cell lymphoma: results from the randomized phase 3 TRANSFORM study. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 91. 

https://ash.confex.com/ash/2021/webprogram/Paper147913.html

Elsawy M, Chavez JC, Avivi I, et al. Patient-reported outcomes in a phase 3, randomized, open-label study evaluating the efficacy of axicabtagene ciloleucel (axi-cel) versus standard of care therapy in patients with relapsed/refractory large B-cell lymphoma (ZUMA-7). Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 430. 

https://ash.confex.com/ash/2021/webprogram/Paper147598.html

Bishop: Tisa-Cel Results Highlight Importance of Time to Infusion

At the 2021 American Society of Hematology (ASH) Meeting & Exposition, a major phase 3 study using chimeric antigen receptor (CAR) T-cell therapy in second-line treatment of aggressive B-cell lymphoma failed to yield positive results. But it’s this trial, the BELINDA study, that may help inform clinicians about the importance of infusing patients quickly, according to the lead investigator.

BELINDA, presented in ASH’s late-breaking session, found that tisagenlecleucel (tisa-cel) had no advantage in event-free survival over standard of care for patients. However, Michael R. Bishop, MD, of the University of Chicago, said it still represents a landmark study that offers many important takeaways, particularly regarding trial design.

Tisa-cel, sold as Kymriah by Novartis, represented an historic breakthrough when it was approved in August 2017. Thus, the news that BELINDA failed to meet its end point—unlike ZUMA-7—was extremely disappointing, Bishop acknowledged in a press briefing.

Could he explain the apparent lack of benefit? “It’s an extremely important question. And if I’m completely honest, I lay awake at night thinking about it,” Bishop said.

He went through possible explanations for gap in results between the 2 trials, starting with their definitions of event-free survival. But the more important differences, he said, have to do with BELINDA’s near doubling in the mean number of days between the time patients were randomized and when they were infused with modified T-cells.

ZUMA-7 did not allow for bridging chemotherapy, only steroids. BELINDA did allow for chemotherapy, Bishop said. Sometimes patients had 2 rounds of bridging chemotherapy. As a result, the median time to infusion for BELINDA with tisa-cel was 52 days. With ZUMA-7 and axi-cel, Locke reported the median time was 27 days.

“There’s a number of variables that affected that,” Bishop said. “And we think this long infusion time, where you have an extremely progressive disease going on, did not permit the potential benefits of tisagenlecleucel. We hope that people will learn from that in the designing of future trials.”

But if the ZUMA-7 findings mean that second-line CAR T-cell therapy could soon be approved by FDA, what can be done to ensure patients are infused in a timely manner? 

) asked Bishop to comment on this, given that the approval of 1 or more CAR T-cell therapies in the second-line setting could open the door to many more patients being eligible for treatment.

Bishop acknowledged that some patients and institutions still have challenges dealing with payers when administering CAR T-cell therapy in the third-line setting, 4 years after tisa-cel’s approval.

“I think it’s quite variable, relative to insurance approval,” he said. “In some situations, I’ll have insurance approval within 48 hours. It really depends upon the carrier. And then there’s other carriers who literally make patients jump through hoops. I think that’s inappropriate for an approved therapy, and especially when you have exactly that—a life-threatening situation. Time is of the essence, and getting that approval and moving forward is very, very important.”

 that payers delays have caused patients to miss the window of opportunity for CAR T-cell therapy. Bishop said in a real-world setting, multiple factors come into play, and payer delays are not helpful.

“Sometimes you can’t wait to get some chemotherapy before [patients] get referred to the [cancer] center,” he said. “And I think that’s also going to be our challenge among physicians who treat lymphoma on a regular basis, especially this patient population.” 

Bishop MR, Dickinson M, Purtill D, et al. Tisagenlecleucel vs standard of care as second-Line therapy of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma: Analysis of the phase 3 BELINDA study. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract LBA-6. https://ash.confex.com/ash/2021/webprogram/Paper155068.html

in Second-line Treatment of LBCL, Kamdar Says

 lisocabtagene maraleucel (liso-cel) offered significant benefits over standard of care (SOC) when given to patients whose large B-cell lymphoma (LBCL) returned or failed to respond (R/R) to the first treatment after 12 months, according to interim findings of the randomized phase 3 TRANSFORM study.

“This is a breakthrough therapy which has shown superiority over SOC in terms of efficacy with an extremely favorable safety profile,” said Manali Kamdar, MD, of the University of Colorado, who presented the TRANSFORM results during the 2021 American Society of Hematology (ASH) Meeting & Exposition. “We are excited about the potential of this study to change the existing standard of care in these high-risk patients.”

All signs point to liso-cel and another chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel (axi-cel), becoming the new SOC options for second-line treatment of patients with LBCL, given the results for liso-cel and those for the phase 3 ZUMA-7 trial.

 Both trials were highlighted at a press briefing to open the ASH meeting. ZUMA-7 later headlined the ASH plenary session (see 

Press briefing moderator Laurie H. Sehn, MD, MPH, a hematologist-oncologist at the British Columbia Cancer Centre for Lymphoid Cancer at the University of British Columbia, called both sets of results “remarkable” and said they would be welcomed by clinicians who feel limited by the current SOC.

“I think it’s inevitable that this will become the standard of care,” she said.

Liso-cel, sold as Breyanzi by Bristol Myers Squibb, was approved in 2021 for adults who have failed on 2 prior treatments for LBCL, based on results of the TRANSCEND-NHL study.

 Investigators have reported that its manufacturing process, which results in an equal balance of CD8+ and CD4+ CAR T cells, makes the product more consistent and less toxic for patients than the first CAR T-cell therapies approved for R/R LBCL.

Use of CAR T-cell therapy earlier in a patient’s course of care was a major theme of this year’s ASH meeting. Kamdar’s press briefing just ahead of her presentation outlined how liso-cel offered significantly improved measures of survival over salvage chemotherapy followed by autologous stem cell transplant, along with better reported quality of life.

In TRANSFORM, 184 patients were randomized to receive liso-cel or SOC. Patients ranged in age from 20 to 75 years; the median ages of patients in the SOC and liso-cel arms were 58 and 60 years, respectively. Two-thirds of the SOC arm was male; the liso-cel arm was 52% female. Patients were well matched by type of non-Hodgkin lymphoma; no racial or ethnic breakdown was reported.

Median event-free survival, the study’s primary end point, was 2.3 months for SOC vs 10.1 months for liso-cel, for a risk reduction of 65% (HR, 0.349; 

 <.0001). Secondary end points all favored liso-cel:

Median progression-free survival was 5.7 months for SOC vs 14.8 months for liso-cel, for a 59% risk reduction (HR, 0.406; 

The likelihood of complete response (CR) was 66% for patients treated with liso-cel, compared with 39% for SOC, for a CR rate that was 27% higher with liso-cel (

 <.00001). Investigators reported that of the 92 patients given SOC, 50 later received liso-cel.

Overall survival data were not mature at the time of data cutoff, but the trend favored liso-cel.

“Despite a relatively short follow-up period of just over 6 months, the positive results of this study suggest that CAR T-cell therapy has the potential to become the new SOC for patients who do not respond to initial chemotherapy or who relapse within 12 months,” Kamdar said.

She pointed out that the patients in the study were very high risk; under current SOC, many do not make it to stem cell transplant. By contrast, in the second-line setting, most did receive liso-cel infusion. When patients are in the third-line or later stage of treatment, a major challenge is that they may be too ill to wait for the CAR T-cell manufacturing process to be complete.

“Of the patients who were randomized to SOC, only 46% were able to proceed to transplantation,” Kamdar said. “On the other hand…97% of patients were able to successfully receive liso-cel infusion.”

 From a safety standpoint, liso-cel was comparable with SOC, and some patients were able to receive the CAR T-cell therapy in an outpatient setting. Although the well-known effects associated with CAR T-cell therapy of cytokine release syndrome (CRS) and neurological toxicity were seen, there were no grade 4 or 5 neurological events. No deaths were attributable to liso-cel treatment.

Investigators reported no new liso-cel safety signals when giving the treatment in the second-line setting. Roughly half (49%) of those receiving liso-cel had some level of CRS, with 37% reporting grade 1 and 11% grade 2; one patient reported grade 3 effects that started on day 9 after treatment and resolved in 2 days. Patients with CRS were treated with tocilizumab (24%) and corticosteroids (17%). The most common treatment-emergent adverse events were cytopenias, which were reported in 43% of patients.

 “For somebody who has to treat patients with LBCL like I do, it’s incredibly frustrating when patients [have] failed frontline therapy,” she said. For patients such as those in TRANSFORM and ZUMA-7, who are especially high risk—Sehn called them “the worst of the worst”—the current approach calls for doubling down with higher doses of chemotherapy. Patients continue to fail, she said.

So, “it’s not surprising that coming in [to the second-line setting] with a novel approach and a cellular therapy that has proven curative capacity [in the] third-line setting, you may have outperformed in with more chemotherapy,” Sehn said.

The word that comes to mind, she said, is that the findings are “logical.” 

Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen reception (CAR) T cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL): results from the randomized phase 3 TRANSFORM study. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 91. 

Locke F, Miklos DB, Jacobson CA, et al. Primary analysis of ZUMA7: a phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standardofcare therapy in patients with relapsed/refractory large B-cell lymphoma. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2. 

Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. 

. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0

Caffrey M, McNulty R. Tanya Siddiqi, MD, discusses the promise of reduced toxicity with liso-cel. 

®. November 24, 2020. Accessed December 15, 2021. 

https://www.ajmc.com/view/tanya-siddiqi-md-discusses-the-promise-of-reduced-toxicity-with-liso-cel

Ongoing and new developments in chimeric antigen receptor (CAR) T-cell therapies were covered at the 63rd American Society of Hematology (ASH) annual meeting. 

ASH 2021 Recap: CAR T-Cell Therapy

POLARIX: Upgrading R-CHOP, Replacing Vincristine With Polatuzumab Vedotin, Improves Progression-Free Survival in DLBCL

The classic chemotherapy regimen known as R-CHOP may get an upgrade for patients who are newly diagnosed with diffuse large B-cell lymphoma (DLBCL), based on study results that showed replacing an old therapy, vincristine, with polatuzumab vedotin (Polivy) improved progression-free survival (PFS) by 27%.

The findings, from the phase 3 POLARIX trial,

 were presented in the late-breaking session of the 2021 American Society of Hematology (ASH) Meeting & Exposition in Atlanta, with sessions also available online. Results were simultaneously published in the 

In POLARIX, an international team of investigators set out to find a better first-line treatment for DLBCL than the combination of rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin hydrochloride), vincristine (Oncovin), and prednisone (R-CHOP) that has long been the default option. Although this combination cures 60% of patients, 40% see their cancer progress and may require salvage therapy and autologous stem cell transplant.

Clinical trial results in the leukemia and lymphoma space were covered at the 63rd American Society of Hematology (ASH) annual meeting. 

January 2022

ASH 2021 Recap: Real-World Evidence

ASH 2021 Recap: Multiple Myeloma

ASH 2021 Recap: CAR T-Cell Therapy

ASH 2021 Recap: Leukemia & Lymphoma

ASH 2021 Recap: Disparities in Care

ASH 2021 Recap: Research From Our Partners