Podcast: ASH 2020 Top Science
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Among the research at this year’s American Society of Hematology (ASH) virtual meeting, investigators presented noteworthy findings on an innovative gene therapy for sickle cell disease, CAR T-cell therapy in high-risk large B cell lymphoma, and research in stem cell transplantation.

In this “in-between-isode” of MedPage Today’s Podcast series, Anamnesis, one of our reporters discusses some of these data.

Host: Hello, and thanks for joining us for the latest in-between-isode of Anamnesis.

ASH 2020 was a virtual event this year due to COVID-19, but MedPage Today’s reporter, Ian Ingram, followed all the major developments from the conference.

Ingram: One notable study at this year’s ASH meeting found that older, high-risk patients with myelodysplastic syndromes, or MDS, lived significantly longer when they underwent allogeneic hematopoietic stem-cell transplantation.

In a multicenter trial of close to 400 patients with intermediate-2 or high-risk MDS based on International Prognostic Scoring System criteria, the 3-year survival reached 48% in those patients with a matched donor who underwent transplant. But in those patients where no suitable donor was found within 90 days, survival at 3 years was only 27%. These patients instead received best supportive care or hypomethylating agents.

Dr. Corey Cutler, of Dana-Farber Cancer Institute, presented the results at a media briefing.

Cutler: This should really be considered part of the standard-of-care landscape for older people with MDS. There really shouldn’t be a bias against transplantation any longer.

Ingram: Cutler said referrals for transplant consideration should occur as soon as possible to best identify suitable candidates.

Cutler: We’d love to see these patients earlier in their disease course, because searching for an unrelated donor among older individuals is not trivial. Older people tend not to have sibling donors that are eligible to be transplant donors, so it does take a longer time to find the appropriate donor.

Ingram: Dr. Lisa Hicks, of St. Michael’s Hospital in Toronto, who moderated the press briefing, highlighted that the findings were similar in patients over the age of 65 compared to those under age 65.

Hicks: The results offer the most definitive evidence to date that this type of treatment — this type of stem-cell transplant — significantly improves the outlook for older adults with high-risk MDS who would otherwise face a high likelihood of dying.

Ingram: Despite prior evidence suggesting a survival advantage, allogeneic stem-cell transplant is not offered to a large proportion of older, high-risk MDS patients. It’s also not covered by Medicare due to a decision by the Centers for Medicare & Medicaid Services, but Cutler suggested this could change.

Cutler: We hope that with the results of this trial showing a definitive benefit in terms of survival, without a detriment of quality of life, that CMS will reconsider their decision ruling on payment for this service.

Ingram: In a study presented during the late-breaking abstract session, a single injection of an investigational viral-mediated gene therapy vector reduced bleeding rates in patients with moderate to severe Factor IX-related hemophilia B by 91%.

The lifelong condition causes bleeding in joints, and patients are destined for severe arthropathy later in life unless they receive regular blood clotting Factor IX replacement therapy.

In the phase III trial presented at a press conference by Dr. Steven Pipe, of the University of Michigan, all but two of 54 patients who were treated with this gene therapy — called etranacogene dezaparvovec — were able to successfully discontinue prophylaxis and have been producing their own Factor IX for 26 weeks.

Here’s Dr. Robert Brodsky, of Johns Hopkins University, who moderated the press conference, highlighting some of the key findings.

Brodsky: In the study, Dr. Pipe and his team found that the majority of trial participants who received the gene therapy are reproducing their own Factor IX for at least 6 months, and the results may open the door for patients previously not included in other gene therapy trials. What’s so important about this study is that with these vectors there was concern about naturally occurring antibodies, and they didn’t exclude people with naturally occurring antibodies. So this is a huge advance in this field.

Ingram: Over 40% of patients in the so-called HOPE B trial had neutralizing antibodies present when they enrolled, but in only one case — a patient with a titer level over 3,000 — did it appear that the antibody level had an effect on treatment. The researchers are now attempting to determine if there’s a certain neutralizing antibody threshold where the product is rendered ineffective.

The other non-responding patient had an infusion reaction and received only one tenth of the active dose. On the other hand, responding patients typically achieved Factor IX expression within the first couple of weeks of treatment, at sufficient enough levels to stop prophylaxis.

Here’s Pipe discussing the implications.

Pipe: I think most people would accept that these are in functionally cured levels — meaning that patients should no longer be bleeding into joints on a regular basis, and my observations from the patients that I follow in this trial is that — they tell me they don’t have to think about their hemophilia anymore. So this is pretty transformative for the overall phenotype for patients — so I think that’s the most encouraging [thing]. And the second thing is kind of a game changer, in not having to screen out patients with neutralizing antibodies.

Ingram: The trial included patients ages 19 to 75, and longer-term experience with gene therapies in hemophilia B appear to suggest long-term durability of responses, with some patients having responses upward of 5 to 10 years. Again, here’s Pipe.

Pipe: I wouldn’t even say that there’s an optimal age that this could become an option. If this ends up being approved in the future, I think this is a real choice that many patients can make at whatever stage of their adult life they’re at.

Ingram: Another study presented at the meeting showed the feasibility of upfront CAR T-cell therapy in high-risk large B cell lymphoma. The study used axicabtagene ciloleucel, otherwise known as axi-cel for short, which is approved in relapsed and refractory disease under the branded name Yescarta.

In 27 patients who were evaluable for treatment response, 85% showed an overall response to the anti-CD19 product, including complete responses in three-quarters of patients. An additional 15% had stable disease after a single infusion.

High-risk large B cell lymphoma patients tend to have poor outcomes, with lower response rates to standard therapies and worse overall survival, and those with early treatment resistance have an increased risk of death.

Here’s investigator Dr. Sattva Neelapu, of MD Anderson Cancer Center, discussing the trial.

Neelapu: ZUMA-12 is the first study evaluating CAR T-cell therapy as first-line therapy in high-risk large B cell lymphoma, defined by both histology and/or IPI and dynamic risk assessment with PET scan after chemoimmunotherapy. Our results show that axi-cel may be safely administered and demonstrates a substantial clinical benefit in patients with an unmet medical need.

Ingram: Patients responded quickly to axi-cel, with a median time to response of 1 month, and about one-fifth of patients who initially only had a partial response or stable disease at the 1-month assessment later converted to a complete response. As this was an early look, about 9 months of follow-up, no survival results were available, but 70% had ongoing responses at data cutoff.

These patients had high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 translocations, and nearly three-fourths had large B cell lymphoma with an International Prognostic Index, or IPI, score of 3 or greater. Median age in the study was 61 years, nearly all had stage III/IV disease, and a majority had double- or triple-hit lymphoma.

Neelapu made a point that while the total infused T cells were comparable to what was seen in the earlier relapsed/refractory trials of axi-cel, the current study showed a higher proportion of a certain type of T cell in the pre-infusion product, which may signal better treatment activity.

Neelapu: In ZUMA-12, we observed a higher frequency of CCR7-positive/CD45RA-positive T cells in the pre-infusion product, which was associated with greater expansion of CAR T cells, suggesting improved CAR T-cell fitness in first-line treatment.

Ingram: In chronic graft-versus-host disease, a JAK inhibitor topped best available therapy as a second-line treatment for adolescent and adult patients who developed the complication after allogeneic stem-cell transplantation.

Here’s investigator Dr. Robert Zeiser, of the University of Freiburg in Germany, discussing this treatment setting at a press briefing.

Zeiser: Chronic GVHD is a life-threatening complication after allogeneic stem-cell transplantation and the majority of patients experience significantly impaired physical, social, and general quality of life. Currently there was no second-line therapy for those patients who had failed corticosteroids in this situation.

Ingram: The phase III trial of more than 300 patients age 12 and over — known as REACH3 — met its primary endpoint. Twice daily treatment with 10 mg of ruxolitinib, an approved drug marketed under the brand name Jakafi, significantly improved overall response rates at week 24 for this group of patients with moderate to severe chronic graft-versus-host disease.

Here’s press briefing moderator Dr. Lisa Hicks, of St. Michael’s Hospital in Toronto, discussing the primary endpoint results.

Hicks: The drug, ruxolitinib, resulted in a 50% overall response rate at week-24 compared to a 25% response with best alternative treatment. The results represent a major step forward for patients with chronic graft-versus-host disease that is not resolved by taking corticosteroids.

Ingram: Treatment also reduced the risk of failure-free survival by 63% over the study period — this was a secondary endpoint defined as no recurrence of underlying disease, need for another systemic treatment for graft-versus-host disease, or death. Median failure-free survival was not reached in the study arm, as compared to 5.7 months in the control arm.

A higher proportion of patients on ruxolitinib also had improved symptoms compared to the control group and were more likely to have complete responses to treatment as well. Again, here’s Zeiser.

Zeiser: The significance of this REACH3 trial is that this is the first phase III trial showing that a new drug, namely ruxolitinib, significantly improved outcomes across a range of efficacy measures in patients with steroid-refractory or steroid-dependent chronic graft-versus-host disease when compared to best available therapy.

Ingram: CRISPR-based gene-editing may offer a cure for people with beta-thalassemia and sickle cell disease, according to preliminary results of two studies.

The trials included a total of 10 patients and involved collecting their stem cells, which were then edited to reactivate production of fetal hemoglobin by using CRISPR-Cas9 technology that targets BCL11A. The modified cells, known as CTX001, were then infused back into the patients, who remained in hospital for about a month to undergo monitoring for engraftment and hematopoietic recovery.

All 10 subjects showed a substantial and sustained increase in fetal hemoglobin production. No vaso-occlusive crises have occurred up to 16.5 months post-infusion in the three sickle cell patients, all of whom had experienced numerous such episodes annually prior to treatment with CTX001. And the seven beta-thalassemia patients became transfusion independent for as long as 20 months following infusion, this after requiring a median of 15 blood transfusions per year before treatment.

Results of the two so-called CLIMB trials were presented by Dr. Haydar Frangoul, of the Sarah Cannon Research Institute.

Frangoul: Our results clearly show that targeting the BCL11A has resulted in a significant elevation in production of fetal hemoglobin in both the beta-thalassemia group and the sickle cell group. We feel that has been advantageous in this setting, and has actually made patients with beta-thalassemia transfusion independent and those with sickle cell disease asymptomatic from their current disease. The sickle cell patients had multiple vaso-occlusive crises pre-infusion of CTX001, and with follow-up up to 16.5 months they have not experienced any pain. So we believe our approach is proving a concept that elevation of fetal hemoglobin can actually improve, clinically, the patients with beta-thalassemia and sickle cell disease.

Ingram: Sickle cell disease and beta-thalassemia can be cured with allogeneic bone marrow transplants, but fewer than 20% of patients have matched related donors, and results with unrelated donors carry higher risks of complication, including graft-versus-host disease and graft failure. Autologous gene-edited cells would have the advantage of being available to all patients.

Briefing moderator Dr. Catherine Bollard, of George Washington University, said the impressive results suggest that gene editing may potentially be a curative option for individuals living with these blood disorders.

Bollard: As a pediatric bone marrow transplant physician who has certainly cured many children with these life-threatening blood diseases, the use of gene therapy like this really opens up a curative approach for many patients who otherwise would not be cured, because they couldn’t cope with an allogeneic stem cell transplant, or they were ineligible from the perspective of not being able to get a suitable donor.

Ingram: The safety profile of CTX001 was similar to high-dose chemotherapy, said Frangoul. One patient had 32 adverse events, and while most were considered low grade in severity, two were classified as serious. In one beta-thalassemia patient, four serious adverse events were considered related or possibly related to treatment. All patients have since recovered.

Host: For more coverage from ASH 2020, you can visit MedPage Today’s meeting page online. Be on the lookout for our next Anamnesis feature coming later this month, and stay tuned for our next in-between-isode, featuring the latest meeting coverage.

  • Ian Ingram joined MedPage Today in 2018 as Deputy Managing Editor, and covers oncology for the site.

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