Page 10 - Haematologica Vol. 109 - July 2024

LANDMARK PAPER IN HEMATOLOGY
M. Eapen
Immunosuppression with posttransplant cyclophosphamide for allogeneic hematopoietic cell transplantation
Mary Eapen
Medical College of Wisconsin, Milwaukee, WI, USA E-mail: meapen@mcw.edu
https://doi.org/10.3324/haematol.2024.285749
©2024 Ferrata Storti Foundation Published under a CC BY-NC license
TITLE
Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplant cyclophosphamide.
AUTHORS
Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ.
JOURNAL
Blood. 2001;98(12):3456-3464. doi: 10.1182/blood.v98.12.3456.
Allogeneic hematopoietic cell transplant for hematologic malignancies can be curative but until about two decades ago was limited to those with a human leukocyte antigen (HLA)-matched sibling or an HLA-matched or mismatched adult donor. Increased access to transplantation in the early 2000s was in part brought about by transplanting bone mar- row from a haploidentical relative. The landmark publication from the Johns Hopkins University School of Medicine in 2001 showed that in mouse models a combination of fludarabine, total body irradiation and cyclophosphamide is sufficient con- ditioning for engraftment with 10x106 major histocompatibility complex (MHC)-incompatible bone marrow cells and that fludarabine can be substituted for T-cell specific antibodies.1 Posttransplant cyclophosphamide decreased the incidence and severity of acute graft-versus-host disease (GvHD) after transplantation of MHC-incompatible bone marrow cells and this was not associated with global immunosuppres- sion, which is consistent with cyclophosphamide’s selective toxicity to T cells activated by antigen recognition (i.e., se- lective toxicity to proliferating alloreactive T cells instead of non-proliferating, non-alloreactive T cells). Reducing the dose of total body irradiation to 200 cGy further minimized the risk of GvHD. The safety and efficacy of the nonmyeloablative conditioning and high-dose posttransplant cyclophosphamide at preventing graft rejection and GvHD after transplantation of bone marrow from a haploidentical relative were studied in patients with advanced hematologic malignancies at the Johns Hopkins and Fred Hutchinson Cancer Research Center (Figure 1).2 Sixty-eight consecutive patients for whom standard allogeneic or autologous transplantation was unavailable or
inappropriate were enrolled between 1999 and 2006. The trial2 concluded that posttransplant immunosuppression with high-dose cyclophosphamide, tacrolimus and mycopheno- late mofetil was associated with low incidences of fatal graft rejection, severe acute GvHD and extensive chronic GvHD, and a suggestion of effective clinical immune reconstitution as evidenced by low rates of severe opportunistic infections. Recurrent disease was the major cause of treatment failure. Nevertheless, the 2-year survival was 36%.
During the same period, at the University of Minnesota John Wagner led a phase II trial of transplantation of two HLA-mismatched unrelated umbilical cord blood units after a nonmyeloablative conditioning regimen and posttransplant immunosuppression with cyclosporine and mycophenolate mofetil, which paved the way for another alternative source of donor cells. In 2006, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) in the USA conducted two parallel phase II trials. Using identical inclusion and exclusion criteria and a common study design, the trials evaluated the effectiveness of haploidentical donor and double umbilical cord blood transplantation for adults with high-risk leukemia or lymphoma who lacked a suitable matched related donor. These multicenter trials confirmed that transplantation of both haploidentical donor grafts and double umbilical cord blood was effective and set the stage for a multicenter randomized trial to assess the relative efficacy of these two alternative sources of donor cells.3 Unlike the timely accrual to the phase II parallel trials, the randomized trial failed to accrue as planned and was closed to further entry of patients by its Data Safety Monitoring Board after having
Haematologica | 109 July 2024
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