CAR T-Cell Therapy Gets a Reality Check—New Guidelines for Europe and Asia— Off-Beat Cancer Research
February 08, 2018
CAR T-Cell Therapy Gets a Reality Check—New Guidelines for Europe and Asia— Off-Beat Cancer ResearchWRITTEN BY: Brian GM Durie MD
The long-term follow-up of CAR T-cell therapy for acute leukemia was just reported in the New England Journal of Medicine. Although this is an anti-CD19 approach, as opposed to the anti-BCMA- directed T cells (CD269) that are now being explored in myeloma, the results are important: they put expectations in perspective amidst the continued overhyping of CAR T-cell therapy for myeloma. (An example of the frenzy is displayed in this over-the-top headline: “CAR T-Cell Therapy an Emerging Explosion in Myeloma Paradigm.”) With current follow-up at about two and half years, the overall results are somewhat sobering: the average remission is 6.1 months and overall survival is 12.9 months.
Despite great optimism, CAR T-cell therapy is not, unfortunately, a panacea for sustained MRD-negativity and cure. It’s important to note that of 83 patients in the NEJM leukemia trial, only 53 moved forward into the planned treatment phase. The exclusion of 30 patients from the outcomes assessment skews the results by including only the patients who were healthy enough to receive the therapy, which takes some weeks to engineer. In standard treatment protocols, all patients are included in data assessments on an “intent to treat” basis--those with high-risk disease along with standard-risk patients on the trial. Clearly the healthier, lower-risk patients included in the outcomes assessment make the treatment look more effective.
The good-risk patients (those with a small amount of leukemia, or “low tumor burden”) were the patients with the very best outcomes, with average remissions of 10.6 months and overall survival of 20.1 months. This best-responding subgroup with low tumor burden was 21 patients (a quarter) of the original 83 patients. The obvious correlation between low tumor burden and deep response to CAR T therapy led researchers to discuss the possible need for “pre-treatment” to reduce tumor burden before CAR T cells were infused. In the leukemia study, some patients also received allogeneic transplant after the CAR T-cell therapy to enhance their response.
The bottom line is that CAR T-cell therapy, like other potential new therapies, is most likely not curative in itself. But unlike other potential new therapies, it is considerably more complex, cumbersome, and expensive. Ongoing and new CAR T therapy trials in myeloma targeting the promising BCMA (B-cell maturation antibody) target on myeloma cells must incorporate these important messages from the leukemia trial, and must address increasing concerns over costs and complexities as well. There must be careful assessment of possible sustained MRD-negative status and identification of patient subgroups most likely to have maximum benefit. As with other therapies, it seems that CAR T-cell therapy in combination with other drugs may turn out to be the better approach.
Other new therapies in myeloma
How do CAR T results compare to results with other therapies? Just last week, we reported the findings from the selinexor trial, in which the average remission for relapsed/refractory patients was five months and survival was over one year. This week, the results of a new trial indicate that remissions again in the relapsed/refractory setting are improved with the addition of bortezomib (Velcade®) to pomalidomide (Pomalyst®) plus low-dose dexamethasone. Exact numbers are not yet available. It is worth noting that carfilzomib/pomalidomide/dexamethasone is also a very active combination.
It had already been reported in 2015 (with a subsequent expansion of the trial to treat 119 patients using the optimal phase II schedule) that average remissions for relapsed/refractory patients were in excess of one year, and survival beyond two years. Newer combinations with daratumumab are equally or more effective. So, I would argue that all new therapies, including CAR T-cell therapies, must be looked at through the same lens of objectivity. What is the response rate? How deep are the responses and how long do they last? And, most importantly with respect to CAR T therapies, what are the toxicities, logistics, and costs compared to other potential options?
Other items in the news this week
By a strange coincidence, both the European Myeloma Network (EMN) and the Asian Myeloma Network (AMN) have just published new guidelines. With many new options for testing, and novel therapies for treatment, these updated guidelines are very important. The AMN guidelines are the second in a series of guidelines from the IMF’s Asian research network, which uses a resource-stratified approach to indicate options for countries and centers with “limited,” “enhanced,” and “maximal” resources. The recommendations are therefore especially helpful in situations where resources are limited, and creating the guidelines focuses on ways to improve resources and outcomes where they are needed most.
Of interest, what is truly a medical research revolution in China is changing the approach to myeloma care in that country. Myeloma expert colleagues in China, members of both the AMN and the International Myeloma Working Group (IMWG), are participating in new research, developing new guidelines, and providing opportunities for gathering new big data.
Amazing new research
Two reports highlight new research that is truly amazing. The first illustrates how light can be used to stop microtubule growth, which in turn can stop cancer cell growth. This is obviously at an early stage but is potentially a non-toxic approach. The second approach looks at body bioelectrics. It turns out that tissue and organ growth and positioning is very much influenced by electricity. Again, it may be possible to use this knowledge to reduce or eliminate tumor growth.
Using the Black Swan-type philosophy, it is crucial to explore all options without judging or knowing the outcomes. Let’s see where these two fascinating research ideas will lead!
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