Updated: Feb 29, 2020
CHICAGO -- Rheumatologists need to take another look at bone marrow transplant as a treatment for refractory autoimmune diseases, a Johns Hopkins University hematologist told a gathering here.
Most of the received wisdom on bone marrow transplant -- that autologous procedures are better tolerated than allogeneic transplants, for example, and that only HLA-matched donations really work for the latter -- is wrong and should be "unlearned," said Richard J. Jones, MD, of Hopkins' Sidney Kimmel Comprehensive Cancer Center in Baltimore.
Those beliefs may have been accurate 20 or 30 years ago, he told attendees at the American College of Rheumatology's State of the Art Symposium, but research and experience gathered in the cancer setting have since upended them. (Though even in oncology not everyone has gotten the message, Jones lamented, noting that a National Cancer Institute website still promotes HLA matching as the gold standard.)
In rheumatologic disease, he said, it's now clear that allogeneic transplant is both safer and more effective than autologous procedures, and that the key is threefold: haploidentical donor selection in place of HLA matching, recognition that graft-versus-host disease (GVHD) is not to be feared, and use of cyclophosphamide post-transplant.
Unpublished early data from his center indicates that in 16 patients with different autoimmune conditions treated under the new paradigm, everyone has so far remained in remission. Hopkins is now about to start a formal trial in scleroderma and multiple sclerosis, Jones said.
The belief that autologous transplant is safer and more effective stemmed from worries over GVHD resulting from the introduction of "foreign" hematopoietic stem cells with allogeneic procedures. But, Jones pointed out, when the goal of transplant is to provide the patient with an entirely new and healthy immune system, that simply can't work when the patient's own, original stem cells are used. Although removal of autoreactive T cells from the patient's autograft may be attempted, it's never entirely successful. He estimated that in an average infusion, something like 20 million autoreactive T cells are likely to be included.
And the fear of GVHD turns out to be unwarranted for a reason many rheumatologists may find counterintuitive -- it's actually desirable. That's because the graft-versus-host reaction "is the only truly ablative modality," Jones said, explaining that it purges the memory lymph cells that perpetuate autoimmunity.
As for HLA matching, that went out the window in oncology years ago, he said. It's simply not necessary -- haploid matching works just as well, and doesn't even need to be perfect, with excellent results seen with up to four mismatched antigens. The one limitation is that donors should not be older than 50 -- but because matches don't have to be perfect, when the most closely matched potential donor is too old, his or her child or even grandchild may be suitable, Jones said.
Another factor contributing to effective immune reset is a nonmyeloablative conditioning regimen pre-transplant followed by cyclophosphamide after transplant. The most desirable cells in an allogeneic transplant, notably the donor's memory lymph cells, resist cyclophosphamide. That's why the drug is not effective by itself long-term in autoimmune disease. But in the post-transplant setting it targets so-called cycling alloreactive T cells that would otherwise interfere with engraftment and promote undesirably widespread GVHD, Jones explained. (Success may be bolstered even further with antithymocyte globulin given prior to transplant and including thiotepa [Tepadina], another myeloablative drug, in the post-transplant regimen along with cyclophosphamide, he said.)
In 2017, his group published results with this approach in 21 patients with relapsed, severe aplastic anemia -- all of whom remain alive and disease-free, Jones said. Two patients experienced mild GVHD that resolved within 18 months. He added that sickle cell anemia also appears amenable to marrow transplant, citing data expected to be published soon.
Outside of formal trials, Hopkins has used haploid-matched donor transplant with cyclophosphamide in six patients with lupus, six with inflammatory bowel disease, three with psoriasis, and one with multiple sclerosis, all apparently successful, although with limited follow-up.
Another advantage of the new approach, Jones said, is that the drugs involved are cheap and easily available -- meaning that it's accessible outside North America and Europe.
Jones said he had no relevant financial interests.