New reduced-intensity, pre-transplant conditioning regimen makes transplant a reality for patients with Dyskeratosis congenita
Dyskeratosis congenita (DC) is a rare, genetically and clinically heterogeneous, inherited disorder affecting one in every million persons worldwide. While bone marrow failure (BMF) is the primary cause of premature mortality, additional clinical complications include pulmonary fibrosis, liver disease, mucocutaneous abnormalities, and cancer. DC patients exhibit abnormally short telomeres; nearly 50% carry known defects in genes required for telomere maintenance.
Telomeres are structures found at the chromosomal termini, comprised of a repeating, hexameric nucleotide sequence. These structures, which shorten with each successive round of cell division, are crucial for protecting the coding region of DNA. In highly proliferative tissues—such as bone marrow, lung, alimentary tract, and skin—enzyme complexes work to prevent the telomere erosion that can lead to cell senescence or death. To date, more than half a dozen genes associated with DC have been genetically characterized, all of which were found to encode components of these enzyme complexes. Presently, hematopoietic cell transplant (HCT) is the only long-term option available for DC-associated BMF. Until about a decade ago, toxicities from pre-transplant radiation and chemotherapeutic regimens, as well as graft-versus-host disease (GVHD), a common side effect of HCT, largely precluded its success in DC.
Building on the rich history of transplantation medicine at the University of Minnesota—the first ever successful HCT was performed here in 1968 by Dr. Robert Good—Stem Cell Institute director, Jakub Tolar, MD, PhD, is leading a team at the Masonic Cancer Center to optimize HCT for patients with DC. The study, which is supported by Intramural Program of the National Institutes of Health and the National Cancer Institute, is developing a reduced-intensity conditioning regimen that, unlike traditional approaches, only partially ablates endogenous bone marrow cells, allowing for more rapid recovery, fewer toxicities, and reduced risk of infection.
Patients with congenital BMF disorders, such as DC and Fanconi anemia, are especially prone to treatment-related morbidity and mortality following the myeloablative conditioning traditionally used in allogeneic HCT for hematologic malignancies. Based on their experiences with severe aplastic anemia and Fanconi anemia, the University of Minnesota team developed a reduced-intensity conditioning regimen for individuals with DC and BMF to promote successful engraftment while simultaneously mitigating toxicities and the risks of GVHD. This DC-specific strategy combines very low doses of cyclophosphamide and lung-shielded total body irradiation (TBI) with fludarabine (a non-alkylating nucleoside analogue that interferes with DNA synthesis and immune responses) and alemtuzumab (a monoclonal antibody targeting various cells of the immune system, including T cells, B cells, and monocytes).
Pre-transplant conditioning of almost two dozen patients with this regimen resulted in overall three- to five-year survival of 85%, a huge improvement over all prior attempts, which led to its adoption as the preferred strategy worldwide. Despite this remarkable success, efforts to improve outcomes continue. Based on collaborations with researchers both in the US and abroad, the group recently began testing a strategy that eliminates the use of TBI, a modification they hope will maintain successful engraftment while simultaneously reducing the risks of lung fibrosis, a complication of DC.
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