Stem cell transplant is still the only curative treatment option for many hematologic malignancies, even as novel drugs continue to emerge.
Even as the US Food and Drug Administration (FDA) approved new agents for multiple myeloma and some lymphomas, stem cell transplant remains the only curative and reliable strategy for these patients.
Signs of this were especially seen in results of the phase 3 StaMINA trial in multiple myeloma, which found that the addition of Revlimid (lenalidomide)/Velcade (bortezomib)/dexamethasone consolidation or a second autologous hematopoietic cell transplant (AHCT) was not superior to a single AHCT, followed by Revlimid maintenance.
Sergio Giralt, M.D., discussed the evolution of stem cell transplant and cellular therapies.
He advises that, “Timely referral to transplant is probably the single most important thing. High-dose therapy and autologous transplant for multiple myeloma remains the standard of care.”
Can you provide an overview on your recent lecture on treatment for hematologic malignancies?
In an interview, Giralt, a professor of Medicine at Memorial Sloan Kettering Cancer Center, discussed the advances in stem cell transplant and how it remains as the sole curative therapy in various hematologic malignancies.I summarized what I thought were the best abstracts from the 2016 ASH Annual Meeting in San Diego in the area of stem cell transplant and cellular therapies. There were some that were really practice changing and probably the start of new eras. Sattva S. Neelapu, M.D., presented the first 51 patients with relapsed/refractory DLBCL treated with a CD19 chimeric antigen receptor (CAR)-modified T-cell therapy. These were dramatic responses; people who had extensive disease achieved complete remissions.
It is still early—most of the patients were not even three to four months out of treatment. The treatment is associated with some toxicities and it probably has to be given in specialized centers. But these are people who had no viable therapeutic option. This is, really, a life-saving treatment.
There were two abstracts in myeloma that called to everybody’s attention. These were long awaited studies. One was presented by the Edward Stadtmauer, M.D. He presented the StaMINA trial, in which 700 patients were randomized to three types of posttransplant consolidation: standard Revlimid maintenance; four cycles of consolidation therapy with Velcade, Revlimid and dexamethasone; and a tandem transplant.
To everybody’s surprise, there was no significant benefit in progression-free survival (PFS) in any of the groups. All of the groups did very well with more than 80 percent having three-year survival and a 56 percent PFS rate at three years. However, none of the more intense arms were superior to Revlimid maintenance alone after autologous transplant. Thus, in North America, we would say the standard of care remains as one autologous transplant followed by Revlimid maintenance for patients with myeloma who are transplant eligible.
Interestingly, this is contrasted from the European trial, which actually showed that there was a benefit for the tandem transplant strategy. Patients who went to a tandem transplant strategy had a better PFS.
What will the role of transplant be in the future?
Why is there the difference between the American trial and the European trial? In the American trial, 32 percent of patients randomized to tandem did not get the tandem arm. Could that explain the difference? We don’t know; we need further follow-up. This question has not yet been totally answered, in that risk-adapted or response-adapted therapy with minimal residual disease (MRD) assessment will be the way we will tailor treatment for patients with myeloma to give them the longest life and best quality of life with a minimum burden of treatment.That is an excellent question. Transplant remains the only curative strategy for many patients with hematologic malignancies. It is the only curative strategy in myelodysplastic syndromes (MDS), in acute leukemia for patients who failed primary therapy, and in high-risk leukemia.
However, it is toxic and it doesn’t work all the time. Relapse remains the most important cause of treatment failure. A lot of these advances will help make transplant easier and make it more effective. Revlimid maintenance is the best example. It doubles the remission duration after transplant and, yet, transplant is an essential component of the long-term disease-control strategy in myeloma.
For those who are ineligible for transplant, what is their best option?
How can we make transplant easier? We are learning a lot about dose reduction, reduced intensity conditioning, and how to best select donors. I am hopeful that, in the next five to 10 years, between outpatient transplant and better ways of managing toxicities and tailoring treatments to the patients, we will be able to improve our safety significantly with having routinely less than 10 percent of the people having serious toxicities after an allograft, and less than 1 percent of people having serious toxicities after an autograft. And, most autographs are being performed as outpatient procedures in this country.That is difficult. We actually think the biggest barrier to transplant eligibility, at this time, is access to a transplant center or caregiver support. Those factors also play into access to good medical care or aggressive treatment. For older patients with MDS, you would think to use hypomethylating agents or supportive care. For older, frail patients with myeloma, you would think about what you would call reduced intensity induction therapy with low-doses of Revlimid /Velcade/dexamethasone. For patients with Hodgkin lymphoma, you see that brentuximab vedotin is very well tolerated in these older groups of patients.
What big misconceptions does the field still have about transplantation?
We now have agents that we can actually use to be able to achieve disease control and actually palliate and, at the same time, we can use combinations of these agents at higher doses to achieve deep remissions and long-term disease control in younger patients and hopefully more cures.That it is only available for young people. We have broken the age barrier; there were more than 1,000 people over the age of 70 transplanted over the last three years with acute leukemia and MDS. We think that this is a very valid option for these patients. Patients with refractory acute myeloid leukemia (AML) have a life expectancy of one year. A 70-year-old who is healthy could have a life expectancy of 15 to 20 years; transplant can actually give them back some of that life.
There is the perception that physicians — who trained many years ago — have that transplant is a very toxic treatment. It has changed dramatically with reduced intensity conditioning, better antibiotics, and better supportive care. It is not a walk in the park, but it’s a lot easier than it was 15 years ago. We expect 15 years from now it will be a lot better tolerated than it is today.
Also, the timing of referral is essential. If you start the transplant consultation the moment you start the induction treatment, you can get 60 percent of the high-risk patients with AML to transplant as opposed to traditionally 30 percent when patients are only referred once they have achieve complete remission.