RIC-HSCT Yields Favorable Outcomes for Patients With CLL-RT

Oscar B. Lahoud, MD, Strategic Partnerships Medical Director, Division of Hematologic Malignancies, Assistant Attending, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, discusses reduced-intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT) for patients with high-risk chronic lymphocytic leukemia and Richter’s transformation (CLL-RT).

Transcript

Hi, I'm Oscar Lahoud, Assistant Attending for the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center for the Division of Hematologic Malignancies.

The existing data was scarce, especially for patients with Richter's transformation. We have encountered patients with Richter's transformation in clinic, and we know that without an allogeneic transplantation, historically, they don't do well.

But we don't know once they proceed with an allo transplant how they perform. We were able to gather our internal institutional data, which has the largest data set of Richter's patients who proceeded to a reduced-intensity conditioning allogeneic transplant.

The other thing I wanted to look at is, with the emergence of novel therapies for CLL, we haven't seen as many referrals for allogeneic transplant, which is good. If we can cure patients without an allogeneic transplant, that would be great. But we want to see where transplants could still fit in within this novel era.

We had a minority of patients, about 11 patients or so, had been exposed to novel therapy and wanted to look at how they fared compared to other patients.

Our findings of the outcome of CLL patients in general that proceeded with reduced-intensity conditioning is pretty consistent with the literature that has been published.

We had an almost 60% 5-year survival rate and between 50% to 60% is what we have seen historically. That was consistent.

The Richter's data was surprising positively.

We thought that Richter's patients have more aggressive biology, and they would have a higher relapse rate, but we had 34% relapse in Richter's and 34% relapse in non-Richter's—it was almost on the dot the same thing. All in all, our Richter's patient did at least as well as our non-Richter's patients, which was a pleasant surprise, and these were true Richter's.

We now consider people with concurrent CLL and DLBCL, for example, that are not closely related to necessarily have poor prognosis than each separate disease individually. Here, whenever we could, we tried to make sure to confirm that it was the same clone that just transformed and evolved into a more aggressive biology.

One thing that was surprising to us in our CLL patients, is when we used conditioning that contained total body irradiation, patients did much poorer in terms of almost every outcome—progression-free survival, overall survival—and that came as a surprise. We had excellent data that we have published previously in non-Hodgkin's lymphoma using this TBI conditioning.

Other institution, like Fred Hutch, have used it. Even the CIBMTR, the Center For International Blood And Marrow Transplant Research, data showed that using TBI conditioning seems to be favorable in non-Hodgkin's lymphoma, and we do not have an answer for why.

When we went back, we saw that the European blood marrow transplant data had previously shown similar findings with TBI conditioning, but in their cohorts, they were using either TBI-containing regimen or fludarabine-containing regimen. Fludarabine is very effective against CLL.

They thought perhaps the TBI patients had not done as well because there was no best therapeutic or cytoreductive effect from the fludarabine conditioning, but all of our patients usually get fludarabine cyclophosphamide and TBI as a package based on our previous data.

That could not be the explanation for it, so we had to try and dig in deeper.

There was some Danish data where they looked at response rates of radiation in general for non-Hodgkin lymphoma. You had to read the paper in more details to see it because it's not highlighted very much. It is a radiosensitive disease, but the CR rate was in the 20-something percent for people who were trying to attempt definite radiation to the site, versus 70% to 80% rate in the other non-Hodgkin lymphoma histologies.

Perhaps there is some more inherent radio-resistance to it. Then there is some in-vitro data suggesting that particularly people with higher-risk cytogenetics tend to have higher resistance to TBI conditioning, and perhaps driving them to more aggressive behavior later on when exposed to it.

All in all, it came as a surprise, and in that sense, it has started to drive our internal practice to no longer use TBI as part of conditioning for CLL patients.

Those were the major unexpected findings.

The application is: How we can advise our patients with Richter's if we are able to get them in a good remission. That has been the consistency with Richter's, CLL, and almost all other non-Hodgkin’s lymphoma histologies.

Getting a patient to good remission and in active response at the time of transplant is one of the best predictors of outcome.

Richter's, because we know that by nature they have aggressive histology, our recommendations would be to proceed at the first remission possible to an allogeneic transplant with a curative intent. Patients do quite well when we get them there early in the course of remission.

That should be the standard practice. People should stop or should be very cautious about using more TBI as part of CLL conditioning regimens.

Some of my colleagues from our institution and others are going to be looking at the registry data from the Center International Marrow Transplantation to see whether that could have been something about the way we perform our transplant at MSK or whether we do see it more globally. Given the European registry data, I think we're going to see it globally, and I think TBI should be permitted as part of intensity conditioning for the CLL patients.

The other tricky part is now our data, and more recently in data published by Dana Farber Institute, shows that novel agents used prior to an allogeneic transplant do not provide any harm to patients and might be of benefit.

Now we have to think especially when we talk about CLL, we are talking about those with high-risk cytogenetics—17p deletions, IgHV unmutated. These are the ones that, despite novel therapies,  have shown great response and tend to work better than classic chemoimmunotherapy, they still do not do as well as patients without those prognostic markers.

In our case, allogeneic transplantation overcomes those poor risk factors. We have confirmed but others too. Whether you have bad cytogenetics or not, an allogeneic transplant doesn't favor one over the other. The key is where we can fit that in with our novel therapy agents.

In our data, patients who had 3 lines or less of treatment did better. In the end, it seems to be the status of disease response. At the time of transplant, that ultimately predicts outcomes.

How we can be generalized is that for those people that we know with standard therapy, have more aggressive patterns of disease, we would refer them for transplant consideration early on with a tentative plan to take them in for a transplant earlier on in their courses of lines of therapy at a time when they are disease-responsive.

Part of the way to expand is based on the limitation of this current study. Its first restrospective, it is a single-institution study, and the numbers are relatively small. We're going to first look at bigger registry data and to see how we can confirm those data.

Now the thing is, from a prospective standpoint, is how we can fit in novel therapies, including, for example, BTK inhibitors? These have had an emerging role in graft versus host disease (GVHD) treatment. Could the incorporation, for example, of ibrutinib, parry transplant, enhance the graf-versus-leukemia effect while reducing the risk of GVHD? Which is still one of the major complications and cause of mortality after another transplant. Now, novel cellular therapies are coming around, like CAR-T cells. Where would those fit in in the management of those patients?

When we think of an allogeneic transplant, especially a reduced-intensity conditioning transplant, the way it works against a disease like CLL is threefold.

One is some cytoreductive treatment as part of the conditioning to reduce the amount of residual disease that is left.

Two is replacing the bone marrow, which is where those leukemic cells are thought to emerge from.

The third part is to replace somebody's immune system, so it is directed against the leukemia, a graft versus leukemia effect, in order to prevent relapse.

That comes at a cost of possible infection from immunosuppression because we are trying to also avoid GVHD, which is that new immune system recognizing our normal cells as different.

One strategy that one of my colleagues here at MSK, Dr. Melody Smith, has come up with is to remove the T cells from the donor and do the standard transplantation. But with those T cells, you re-engineer them as CAR-T cells so that you maintain the graft-versus-tumor effects while reducing the risk from GVHD.

I would like to thank the person who has mentored me for years, Dr. Craig Souder, who is a senior author on this paper. He is the one who had led the trial of our non-Hodgkin’s lymphoma conditioning with Flu/Cy/TBI several years ago. He has been a fantastic mentor throughout this process. All my other colleagues and faculty and mentors at MSK, all our patients, and our lymphoma and leukemia colleagues who have referred those patients.