An expert on graft-vs-host disease provides an overview of GVHD prophylaxis and conditioning regimens prior to transplant.
Case: A 48-Year-Old Man with Chronic GVHD
Yi-Bin Chen, MD: In terms of the conditioning regimens we might use prior to transplant, historically there was a polarity of very intense conditioning regimens called myeloablative, then very nontoxic regimens labeled nonmyeloablative were created. Then we started to move toward the middle, where reduced intensity/reduced toxicity regimens were created. The very conventional myeloablative regimens were either high-dose Cytoxan with myeloablative total body radiation, meaning doses of 1200 to 1400 centigrade of radiation, or high-dose busulfan with high-dose cyclophosphamide. The nonmyeloablative regimens were based on work done by colleagues at the Fred Hutchinson Cancer Center in Seattle, Washington, being fludarabine with low-dose total body radiation, around 200 centigrade. But most of us have moved toward the middle a bit. We’ve realized that high-dose regimens, on the far end of the spectrum, do not necessarily translate into better outcomes. They definitely have more toxicity compared to our less intense regimens. We’ve realized that high-dose total body radiation has unacceptable long-term effects and probably only benefits patients with acute lymphoid leukemia.
For our standard options for a myeloid malignancy, if we’re going to use myeloablative conditioning¾which we should to reduce the risk of relapse, based on randomized phase 3 data¾we tend to lean toward high-dose busulfan paired with fludarabine. That is more of a reduced toxicity regimen. If the patient was a bit older, had some comorbidities we were worried about, or had a tough time with their induction chemotherapy and weren’t fully recovered, we would use a combination of fludarabine and melphalan, which is technically considered reduced intensity, but certainly is far more intense than the nonmyeloablative regimens. For the fludarabine-melphalan combination, we’d dose at melphalan 100 mg/m2. Then going down the line in terms of the spectrum, fludarabine paired with reduced intensity busulfan at half the dose of myeloablative busulfan, and so forth. It has become more of a continuous spectrum. There are multiple published regimens that different centers use. I think all of us are trying to hit the balance of providing a good amount of cytotoxicity to help prevent relapse, as well as engender engraftment, and at the same time, not accrue significant off-target toxicity.
Inherent to every allogeneic transplant is a risk of acute or chronic graft-vs-host disease [GVHD]. The reason behind this is that we undertake a transplant partly because the conditioning regimen is able to deliver more therapy against the malignancy, but the main mechanism of action of an allogeneic transplant is an immunological graft-vs-malignancy effect. That means that once the donor cells grow up and reconstitute a hematopoietic and an immunological system in the recipient, we hope that if there’s any residual malignancy left, those donor cells are able to eradicate that through graft-vs-malignancy. This is perhaps the purest and earliest form of immunotherapy that has existed in oncology. However, with that immunological effect, there is a risk of acute and chronic graft-vs-host disease, meaning the donor’s immune cells attack the recipient’s healthy body.
Every transplant requires some form of prevention against graft-vs-host disease. There are 2 general methods. One option is far more complicated, which is called ex vivo T-cell depletion or graft manipulation, meaning that the cell therapy laboratory at each institution is able to manipulate the graft through either positive or negative selection. Eliminating certain cellular subsets can possibly prevent graft-vs-host disease. That obviously requires a more expensive infrastructure as well as experienced technicians who are able to perform that type of manipulation. There are plenty of investigations going on to figure that out.
The more common—by far—form of graft-vs-host disease prevention is called pharmacologic therapy. The historical standard has been the combination of a calcineurin inhibitor, being either cyclosporine or tacrolimus, paired with either methotrexate or mycophenolate. More recently, colleagues have innovated and brought into practice a regimen built around high doses of post-transplant cyclophosphamide. This regime is given on days 3 and 4 after transplant and paired with tacrolimus and mycophenolate after.
These are the main regimens in use. There are several large clinical trials comparing these regimens to each other. Other clinical trials are adding to these standard backbones. It’s difficult to predict one to the other. There have been very few prospective trials comparing one regimen to the other, but they do exist. Usually, the regimens have been chosen based on the donor a patient has for the transplant. In terms of success, overall, the literature would quote about a 40% to 60% risk of acute graft-vs-host disease, and a long-term risk of about 40% to 50% of chronic graft-vs-host disease that we would need to do something about. Those are historical figures. I think the modern figures are less, with the advances in GVHD prophylaxis. I think those numbers tend to also move by how aggressive each center is at diagnosing graft-vs-host disease.
Transcript edited for clarity.