The Next 'Big Thing' for Blood Cancers Featured at ASH 2019

Zosia Chustecka

December 07, 2019

The prospect of an "off-the-shelf" product, rather than one that needs to be grown individually for each patient, is a "very exciting" proposition, say experts discussing new data that will be presented at the forthcoming American Society of Hematology (ASH) meeting.

For the last few years, much attention has been focused on chimeric antigen receptor (CAR) T cell products for the treatment of leukemias and lymphomas.

These products have been taking center stage at the meeting, mainly "because of their incredible efficacy," commented ASH Secretary Robert A. Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine in Baltimore, Maryland.

"But there are several drawbacks, and one of these is the time and expense that it takes to generate a CAR T cell product for a specific patient," he said.

It can take 2 weeks to make such a product, as the process has several key steps. Blood taken from the patient needs to be prepared, packaged, and sent to a specialized manufacturing facility, where the cells are genetically engineered and expanded in culture, and then the product — prepared specifically for that one individual — is transported back and administered to the patient.

In that time, the patient may deteriorate, and even die.

These are patients who have already exhausted all other forms of therapy, Brodsky noted. "Only two thirds of patients who are enrolled...actually get them."

That's why the prospect of an off-the-shelf product that could be used immediately is so appealing.

One approach is aimed at developing generic CAR T cells that could be used for all patients (instead of individualized products).

And one such project, the first-of-its-kind multiantigen targeted off-the-shelf CAR NK cell with engineered persistence for the treatment of B cell malignancies (being developed by Fate Therapeutics, featured in abstract 301) has demonstrated proof of concept, commented Brodsky. Clinical trials are now being planned.

However, another approach is much further along the development path, with results already from a large phase 2 trial that are "very exciting," said Brodsky.

The work has been selected for the plenary session — which highlights only six abstracts from the 4900 presented — and will feature mosunetuzumab (Genentech/Roche, abstract 6).

Mosunetuzumab is a bi-specific antibody that targets both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). It redirects T cells to engage and eliminate malignant B cells, the research team explain in the abstract.

"The concept here is that this monoclonal antibody engages T cells and directs their cytotoxicity against B cells — it's basically an antibody using the patient's own T cells to do what a CAR T cell would do," Brodsky explained.

The trial to be presented was conducted in 218 patients with relapsed/refractory non-Hodgkin's lymphoma, of whom 23 patients had already been treated with CAR T cells, so these are very refractory patients, he pointed out.

The results show that 64% of patients responded and 42% had a complete response, and the duration of response is now out to 9 months, he said.

"This a very exciting study, and it is a large study," Brodsky commented, pointing out that some of the early trials with CAR T cells were conducted in only 20 to 30, sometimes 50, patients. "So what this tells you is that this is far more accessible," he added. This is a product that can be used immediately in all patients.

There are still many questions about this approach: Will it be as effective as CAR T cells? Is it going to be that much cheaper? Is it going to be durable?

Brodsky said that future trials will need to explore these issues, but the data so far are "very promising."

For now, he added, "I think CAR T cells are here to stay. The question is, are these bi-specific antibodies going to encroach on their use?"

Brodsky also mused about whether history was going to repeat itself. He recalled that in the 1980s and 1990s, there was a push to make patient-specific monoclonal antibodies to treat lymphomas, particularly low-grade lymphomas, but "you don't hear about that anymore, and the reason is rituximab," he said.

Rituximab (Rituxan, Genentech/Roche, now also available as biosimilars) is a monoclonal antibody directed against CD20 on B cells widely used in the treatment of B cell lymphomas.

"It turned out to be effective in most patients, and it was easier and cheaper to manufacturer than making patient-specific antibodies," Brodsky commented.

The question right now is whether bi-specific antibodies will do the same, he continued.

"These bi-specific antibodies are encroaching into the domain of the CAR T cells. If they can do the same thing that the CAR T cells can do, they will be a big advance," Brodsky commented. "But so far we just don't have the data to say that history is going to repeat itself."

Largest Hematology Meeting in the World

Brodsky was speaking to journalists during a preview webinar ahead of the ASH annual meeting, which will take place December 6 to 10 in Orlando, Florida.

With more than 25,000 attendees expected from over 115 countries, "this is the largest hematology conference in the world," said Aaron Gerds, MD, from the Cleveland Clinic in Ohio, who is chair of ASH's committee on communication. "It's really a great meeting of the minds," he added.

Several of the presentations will be practice-changing, commented current ASH president Roy Silverstein, MD, department of medicine, Medical College of Wisconsin in Milwaukee.

Among them are two presentations that will feature venous thrombosis, both deep vein thrombosis and pulmonary embolism. This remains a "very significant clinical and public health problem," he said, with more than 900,000 cases per year in the United States.

The problem is rare in children, he continued, but it "is a real problem" in children who are hospitalized, for example, because of congenital heart syndromes and those with cancer, many of whom require indwelling catheters. The standard treatment has been low molecular weight heparin, but this requires daily or twice-daily subcutaneous injections, which is not easy to do in these chronically sick children, he added.

New data from the Einstein-Jr phase 3 trial (abstract 164) conducted in 350 children have shown equivalence for a new liquid oral formulation of rivaroxaban (Xarelto, Janssen) with dosing calculated by body weight.

"This will, I believe, be the new standard of care," Silverstein predicted. He noted that this pediatric indication is "not yet FDA approved, but we should expect that relatively quickly."

The other data Silverstein predicts, or maybe hopes, will change practice comes from a study showing a lack of benefit, and potential harm, from aspirin use in patients who are already taking direct oral anticoagulant (DOAC) therapy (abstract 787). These new agents are now being used to treat patients with atrial fibrillation and acute or chronic venous thrombosis disorders, but out in the community many of these patients are also taking aspirin, in many cases for reasons that are not really indicated, he commented.

The study looked at 645 patients being treated appropriately with DOAC but also taking low-dose aspirin. Investigators found that, although there was no impact on the rate of recurrent thrombosis or stroke, there was an increase in clinically relevant nonmajor bleeding resulting in increased physician visits and hospitalization.

"This is good evidence for our community physicians that patients on DOAC do not need to be on aspirin unless there is a clear indication or good reason, such as a recent stenting or a myocardial infarction coronary disease," Silverstein commented.

Practice-Changing Abstracts on Two Leukemias

Several of the late-breaking abstracts will feature clinical trial data that are likely to change clinical practice, noted Brodsky.

One of these features blinatumomab (Blincyto, Amgen), described as a bi-specific T cell engager (BITE) antibody, which is already approved for use in relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL).

"ALL has been a very curable disease in children and young adults, but a significant percentage of these patients relapse, and when they do it's a real problem," Brodsky explained. "At that point, the major emphasis is trying to get them back into full remission and get them to a transplant," he continued, "but it's very hard to get these patients back into remission."

The new data comes from a randomized phase 3 trial in 288 children, adolescents, and young adults with a high- or intermediate-risk first relapse of ALL who underwent post-reinduction consolidation prior to transplant with either blinatumomab or standard chemotherapy (abstract LBA1).

The results showed that 73% of patients on blinatumomab versus 45% on standard chemotherapy were able to proceed to transplant, and the product was also less toxic and led to longer progression-free and overall survival compared with chemotherapy, Brodsky said.

"This is truly practice-changing," he commented, adding that blinatumomab "is clearly going to become a new standard of care in relapsed/refractory ALL."

Brodsky also predicts a practice change in the treatment of acute myeloid leukemia (AML), reacting to data from the phase 3 QUAZAR trial in which an oral liquid formulation of azacitidine (CC-486, Celgene) was used as maintenance therapy (abstract LBA3). 

The trial was conducted in 472 patients with poor-risk AML in first remission. "It's not too hard to get these patients into remission," commented Brodsky. "The problem comes in keeping them in remission."

The new data show that azacitidine improved outcomes compared to placebo plus best supportive care in terms of median overall survival (24.7 vs 14.8 months) and median relapse-free survival (10.2 vs 4.8 months).

"This is a practice-changing trial in adults with poor-risk AML," said Brodsky.

Celgene announced topline results from the trial in September 2019 and said at the time that it plans regulatory submission for CC-486 in the first half of 2020.  

Another late-breaking abstract Brodsky highlighted features a new triplet combination for use in multiple myeloma. The phase 3 CANDOR trial in 466 patients with relapsed/refractory multiple myeloma investigated the addition of daratumumab (Darzalex, Amgen) to carfilzomib (Kyprolis, Amgen) and dexamethasone (abstract LBA6).

Triplet therapy with daratumumab, carfilzomib, and dexamethasone showed "markedly improved" progression-free survival compared with the doublet of carfilzomib and dexamethasone (median not reached vs 15.4 months). The triplet also achieved deeper responses, Brodsky noted, and he predicts the triplet will be practice-changing for this patient population.

Amgen released topline results from the trial in September 2019 and said it is preparing regulatory submission based on these data. At present, daratumumab is approved for use in relapsed/refractory multiple myeloma as monotherapy, in combination with dexamethasone, or with dexamethasone and lenalidomide.  

Fast-Moving Field

Silverstein commented that, in addition to all the new data that will be presented, the meeting also has numerous educational sessions. New clinical guidelines will be released and recommendations have been updated, sessions that are very popular with attendees, he said. He described these sessions as "practice-enhancing," adding that clinicians have said they find "these sessions very helpful in enhancing care of their patients."

Hematology is a very fast-moving field and everyone in it needs to keep up and keep abreast of developments, Silverstein commented. The ASH meeting is the place to do so, he suggested.

Medscape Medical News will have a team of journalists at the meeting reporting on the new data as it is presented. If you are at the meeting, please stop by and say hello at the Medscape booth (#423).

Silverstein reports equity ownership in Pfizer; Gerds reports relationships with Apexx Oncology, Celgene, CTI BioPharma, Biosciences, Incyte, Roche, and Samus Oncology; Brodsky reports relationships with Achillion, Alexion, and UpToDate.

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