GVHD Outcomes of Busulfan Plus Fludarabine for Older Patients With Hematologic Malignancies

Uday R Popat, MD, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, overviews the long-term disease outcomes from a phase 2 prospective clinical trial on myeloablative fractionated busulfan with fludarabine in older patients with hematologic malignancies.

Transcript

Dr Popat:  Hello. My name is Uday Popat. I'm a faculty and deputy chair at interim in the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center at Houston.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Popat: There is an unmet need for better conditioning or preparative transplant regimen for older patients who undergo stem cell transplantation.

Generally, we say that about 40% of the patients would have MDS or AML who receive current reduced intensity regimens are cured of their disease. About a third of them failed because of treatment related complications, mobility, and mortality. A third fail because of relapse or recurrence of the original disease. Certainly there is a need to improve those outcomes from 40% to higher.

Now, we have been thinking a lot about it and borrowing from other fields of research in oncology. This idea came to us from AML studies done early on at Hopkins, where they developed what is called a sequential therapy. Their idea was to give a course of chemotherapy and follow it up later or a week later with another course of chemotherapy. What they showed was the efficacy was better. This was subsequently taken in a randomized trial in AML and showed that the 2 courses given back to back 1 week apart did improve the outcomes compared to you waiting for say 4 weeks or so.

There was a merit to giving the chemotherapy regimen in a fractionated manner. Now, traditionally with stem cell rise transplant regimen consists of a course of chemo and/or radiotherapy over a period of 6 to 7 days. Then, once the chemo is out of the system, we give the cells back. So we said, “Could we use the same principles and maybe split the dose of chemotherapy or fractionate it over a 2 week period instead of a 1 week period?”

That was our first study. At that at time what we did was we took the traditional reduced intensity regimen that we were using. We used this regimen, and we also asked the question, “could we increase the intensity of this regimen and therefore give more chemotherapy to these older patients or myeloablative dose of chemotherapy toward the patients?”

Then, the first study we showed that interestingly and surprisingly, if you have a gap of 1 week between 2 courses of chemotherapy, or if you fractionate the busulfan, which is the main drug that is used, and give it over a 2-week period, we saw significant reduction in the toxicity. Because there was significant reduction in the toxicity, we could give my ability doses to patients as old as 75. That essentially is what we are showing in this particular paper.

OLN: Could you briefly describe the study and its findings?

Dr Popat: In this current study, we built upon our previous study where we showed that myeloablative dose, and here the myeloablative dose refers to dose of busulfan with the area under the curve of 20,000 micromoles per minute could be safely given. So, what we said is that, let us give this to a group of patients in a phase 2 manner, patients who were older and patients who have comorbidities and who are eligible for traditional reduced intensity regimen. Traditionally in most centers, even today, somebody who is older and 60 or 65, or somebody who has comorbidity, will get reduced intensity regimen. Then specifically, one of the commonest regimen is could have been busulfan. Typically, patients will get half dose of busulfan. What we said was we will give the full dose of Busulfan, but with two changes, 1, we will check their blood drug levels and dose it based on the pharmacokinetic guidance.

Second, we will give myeloablative dose, but give it over a 2-week period. So, a third of dose of busulfan, we give it on the minus 12 minus 13, which is where day 0 is the day of transplant. The rest of the conditioning regimen was given from day minus 6 to 2 as is done conventionally. Essentially it is if you will be fractionated the busulfan and gave myeloablative dose to patients who are candidate for traditional reduced intensity chemotherapy.

In this study, we have a reasonably long follow up now. With a median age of 61, we show that in patients with AML in first complete remission, the CR rate and long term survival rate is more than 66%. If this patients with AML who have 1 negative for minimal residual disease, or so called MRD negative, the long-term survival rate is more than 80%. This data were very encouraging and that's why this is something that we have taken on further at our center.

OLN: Were any of the outcomes particularly surprising?

Dr Popat: What was the most surprising and probably what would be most astonishing to most people is we are giving the doses of fludarabine and busulfan to our 75 year old or say 70 year olds that most people would only give it to patients younger than 60.

Only difference is No. 1, we check drug level and to pharmacokinetics. No. 2, we give it over a 2-week period. The essential difference is this: it's a very simple thing if you think of about it, you're giving the same treatment, you're just giving it a longer period. But that has tremendous impact. That was to me, a very surprising finding.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Popat: Clinically at MD Anderson these days, we are using this regimen for our patients with myeloid malignancies and even ALL for, and more, both younger and older patients. We are seeing increasingly good results. So this then has become, at least, at our center the go-to regimen.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what will be your next steps?

Dr Popat: In fact, this study we started almost a decade ago. It is the protocol number was 2011 0 958. The study started in 2012 and we just published the data. But once this study was over, we thought how could we improve upon this?

So we went back to the drawing board to see where the problems with this regimen were. We found that we still had higher non-relapse or treatment related mortality. It was still 20%-25%. The relapse rate was also high in certain subgroup of patients who are at high risk of relapse. We obviously needed to improve it further. The first thing we did to reduce the non-relapse mortality was to ask the question, what was causing it? It turns out it was caused by graft versus host disease (GVHD). In other words, it was a better way or better GVHD prophylaxis.

Around the same time, a lot of encouraging data for haploidentical transplant using post-transplant cyclophosphamide were available. We thought maybe using post-transplant cyclophosphamide as GVHD prophylaxis would further reduce GVHD and thereby treatment related mortality. And we added that.

What this also allowed us to do was to use this regimen in recipients of haploidentical donors as second. And third, we said if a 2 week regimen is better than 1 week regimen, could we do a 3 week regimen, which may be better than 2 week regimen?

The answer to all these questions we have presented in some preliminary reports at various medical meetings. What we found is that our non-relapse mortality goes down significantly to 10% or less. We've also found that further fractionation leads to further reduction in toxicity. The next step was how could we go ahead and reduce the second reason for failure, which is relapse?

We said, obviously we needed to add something more to fludarabine and busulfan. We started with several different agents. We added cladribine to this regimen. In another iteration of this studies, we added thiotepa to this regimen, which so double alkylating agent or double nucleoside to see if that would make a difference.

And finally, more recently, one of the beautiful thing about a 3 week regimen is, it is during this 3 week period you can gave another oral targeted therapy during this period. We have added sorafenib, we've added venetoclax. There are various phase 2 studies that are undergoing and we are fine tuning it. Some of the data we have presented in a preliminary fashion, but I'm happy to say that we are seeing some sign of further reduction in relapse.

Once the data matures, we will be publishing these at future meetings.

OLN: Is there anthing else pertaining to your research and findings that you would like to add?

Dr Popat: This is a very, very simple and basic idea. All we are doing is giving our treatment regimen over a longer period.

Amazingly, we are seeing some very nice results. Sometimes the solution to a difficult problem may not be complicated—it could be simple. I think this is something worth trying this idea or this concept. I would urge your listeners to consider this.