What's Hot at This Year's ASH Meeting?

Zosia Chustecka

November 23, 2018

The premier event in hematology is celebrating its diamond anniversary. This will be the 60th annual meeting of the American Society of Hematology (ASH). It will be returning to the city of San Diego, California, and will run from November 30 to December 4.

More than 25,000 attendees from 155 countries are expected, and more than 4800 abstracts will be presented, Aaron Gerds, MD, chair of ASH's Committee on Communications, said at a media briefing.

Big Trials, Big Results

The meeting will feature "big trials with big results," said ASH secretary Robert Brodsky, MD. He highlighted several (described below) that "are almost certainly going to be practice changing."

The FLYER trial from Germany (abstract 781) showed that it is possible to de-escalate treatment of favorable-prognosis diffuse large B-cell lymphoma in younger patients (18 to 60 years) without losing efficacy.

The standard treatment is six cycles of rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP). But the FLYER investigators report that four cycles of R-CHOP and two of rituximab alone are noninferior.

"This is important because the chemotherapy can have late effects, such as cardiotoxicity from the doxorubicin, and years later there can even be the risk of secondary malignancies," commented Brodsky. "So for younger patients, it is a big advantage to de-escalate therapy," he added.

The other big trial is a phase 3 study conducted by the National Cancer Institute (NCI) Clinical Trials Network that will establish monotherapy with the targeted therapy ibrutinib (Imbruvica, Pharmacyclics) as a standard of care for older patients (>65 years) with previously untreated chronic lymphocytic leukemia (CLL) (abstract 6).

Until now, chemoimmunotherapy has been the gold standard, and in this study, bendamustine with rituximab was used as the control arm. The two experimental arms used ibrutinib alone and ibrutinib in combination with rituximab.

Ibrutinib is not a chemotherapy; it is a Bruton tyrosine kinase inhibitor that depletes B cells. The results show that this drug used alone yielded the longest progression-free survival (PFS) of the three treatment arms.

The other trials that are likely to change clinical practice, according to Brodsky, will be presented as late-breaking abstracts on Tuesday, December 4. The abstracts, which have not yet been published online, will report on the following:

  • Another trial of ibrutinib for the treatment of CLL in younger patients with previously untreated disease, in which there was an improvement in overall survival (abstract LBA4).

  • The CASSINI trial of rivaroxaban (Xarelto, Janssen) for preventing venous thromboembolism in high-risk ambulatory patients with cancer (abstract LBA1).

  • The PAUSE study, which investigated treatment interruption for elective surgery in patients with atrial fibrillation who were taking a direct oral anticoagulant (DOAC) such as rivaroxaban and apixaban (Eliquis, Bristol-Myers Squibb) (abstract LBA5).

  • Details of safety and efficacy (abstract LBA6) for emapalumab (Gamifant, Novimmune), an interferon gamma–blocking antibody, which was recently approved in the United States and is the first treatment approved specifically for primary hemophagocytic lymphohistiocytosis. This is an extremely rare, rapidly progressing, often fatal syndrome of hyperinflammation thought to be driven by hyperproduction of interferon gamma and that ultimately leads to organ failure.

Introducing a New Drug — Luspatercept

Making a debut at the meeting will be a new drug, luspatercept (under development by Acceleron and Celgene), a first-in-class erythroid maturation agent that enhances late-stage erythropoiesis.

Two phase 3 trials to be presented at the meeting will show that it significantly reduced the need for red blood cell transfusions in comparison with placebo in two separate patient populations.

In the Medalist trial, this benefit was seen in patients with myelodysplatic syndrome (MDS) (abstract 1). Patients selected for this study had very-low-, low-, or intermediate-risk MDS with ring sideroblasts. The patients had refractory disease or were intolerant of or ineligible to receive erythropoiesis-stimulating agents.

The Believe trial showed this benefit in adult patients (>18 years) with β-thalassemia (abstract 163). These patients had β-thalassemia or hemoglobin (Hb) E/β-thalassemia. The trial included patients with compound β-thalassemia mutation and/or multiplication of α-globin genes.

It appears that luspatercept can improve the production of endogenous red blood cells by enhancing the maturation of these cells in the bone marrow, explained ASH President Alexis Thompson, MD. The drug significantly reduced the need for red blood cell transfusions, and "this is a very exciting advance for patients who would have few other treatment options," she said.

The drug is moving toward approval in the United States and elsewhere; "this is one to watch out for, as it is potentially practice changing," Thompson added.

Update on CAR T-Cell Therapy

Chimeric antigen–receptor (CAR) T cells have been the big story at the past few ASH meetings. The therapy has shown some remarkable results in patients with very refractory disease.

However, this technology is still relatively new — the first patient received a CAR T cell in April 2012, so the longest follow-up is only 6.5 years. There are still many questions as to the ultimate fate of these genetically engineered T cells in the body, as well as how patients fare in the longer term, commented Brodsky, so there is an eager audience for outcome results.

Some longer-term data will be provided in two presentations featuring tisagenlecleucel (Kymriah, Novartis), the first of the CAR T cells to be approved.

One will report data from its use in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) from the ELIANA trial. These data come from 79 patients; median overall survival (OS) has not yet been reached; OS probability at 18 months is 70% (abstract 895).

The other reports on its use in adult patients with r/r diffuse large B-cell lymphoma from the JULIET trial. These data come from 115 patients. No relapses were observed beyond 11 months after infusion; OS probability was 48% at 12 months and 43% at 18 months (maximum follow-up = 29 months) (abstract 1684).

"As we get further and further out, it is encouraging that there are durable responses," commented Brodsky.

When the CAR T cells were approved last year, the very high price tag drew sharp intakes of breath (tisagenlecleucel costs $475,000). One argument put forward to justify the expense is that this approach offers the chance of a cure after only one infusion.

However, there is still a question as to whether CAR T cell treatment on its own is enough or whether it should be seen as a "bridge" and that treatment should be consolidated with a bone marrow transplant.

New data presented at the meeting (abstract 967) hints that transplant consolidation improves leukemia-free survival. These data come from the Seattle Children's Hospital, where the current institutional recommendation for r/r ALL patients who have not received an allogeneic hematopoietic stem cell transplant is to undergo a transplant once they are in remission following CAR T-cell therapy.

Brodsky commented that this is a very small study at a single institution and that the data are retrospective, but the data do suggest that a transplant may be a good way to consolidate the remission seen after a CAR T-cell therapy.

Two small studies explored adding other modalities to the CAR T cells in an effort to reduce toxicity and/or improve efficacy.

One study (abstract 299) investigated adding ibrutinib. Treatment with the drug was initiated even before electrophoresis to collect the T cells for manipulation and was continued during CAR T-cell therapy. This is a very small study, with 36 patients in total, but there is a suggestion that irbrutinib was able the reduce some of the side effects of CAR T-cell therapy, particularly cytokine release syndrome. There was also a suggestion that it may improve response, said Brodsky.

Another small study (abstract 556) explored adding the immunotherapy checkpoint inhibitor pembrolizumab (Keytruda, Merck & Co). The hope was that when the CAR T-cell therapy starts to fade and the patient faces a relapse, the checkpoint inhibitor would take the brakes off the immune system so as to boost the response, Brodsky explained. This is indeed what appeared to happen in about half of the patients, although this was a very small study with only 14 patients, he noted.

For both of these small studies, the data are preliminary, but both are "very exciting," he said.

Special Educational Sessions

In addition to specific abstract presentations, the meeting will have special educational sessions, noted ASH President Thompson. One will update delegates on the latest developments in the treatment of sickle cell disease. Another will outline details of the ASH new clinical practice guidelines on the management of venous thromboembolism, which have just been launched and are the culmination of several years of discussion, she said.

In addition, there will be special sessions with guest speakers. This year, ASH will host NCI Director Norman "Ned" Sharpless, MD, PhD, on Saturday, December 1. In addition, National Institutes of Health Director Francis S. Collins, MD, PhD, will be talking about accelerating cures in the genomic age on Tuesday 4 December.

At the meeting, a team of Medscape journalists will be reporting the news as it breaks, as well as reactions to it and expert opinion on how the new data can be incorporated into clinical practice, so be sure to check back here regularly to keep up to date.

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