Case study 68.1
You are consulting a 54-year-old man for consideration of hematopoietic cell transplantation (HCT) as therapy for high-risk acute myeloid leukemia. He asks how you plan to collect stem cells for his transplant and how that may affect his risk for posttransplant complications. He has read about graft-versus-host disease (GVHD) and is particularly fearful of this transplant complication.
1. True or false? Peripheral blood stem cell (PBSC) grafts are associated with an increased risk for acute GVHD when compared to bone marrow grafts.
- True
- False
Although some initial studies implicated that PBSC grafts imparted greater risk for acute GVHD, larger and more recent randomized studies have shown no difference in risk between bone marrow and peripheral blood grafts, which report GVHD rates of 50–80%. In a recently completed randomized clinical trial specifically designed to compare the two graft sources from unrelated donors, however, patients receiving marrow grafts experienced increased graft failure (9% vs. 3%; P = 0.002) and decreased risk for chronic GVHD (41% vs. 53%; P = 0.01) when compared to those receiving PBSCs. The 2-year incidence of relapse (approximately 25%) and rates of overall survival (approximately 50–55%) appear to be comparable between graft sources.
Umbilical cord blood offers a potential graft source for patients who do not have suitably matched donors. Transplants using single umbilical cord blood units confer decreased risk for GVHD when compared to blood or PBSC grafts regardless of whether the donor is related or unrelated (hazard ration (HR): 0.4–0.45). Importantly, GVHD risk from cord bloods mismatched at up to two loci at human leukocyte antigen A (HLA-A), -B, or -DRβ1 is comparable to that of fully HLA-matched unrelated donor marrow or PBSCs, and risk was less than that from HLA-mismatched unrelated donor marrow or PBSCs (HR: 0.66). The decreased absolute number of T-cells and the predominance of naïve T-cells in the graft may explain why cord blood grafts are more tolerant of HLA disparity than marrow or PBSC grafts, and delayed count recovery and increased infectious complications are observed after cord blood transplantation.
The small cell dose available from a single cord blood unit is often insufficient for adult patients and obese children; the minimum acceptable pre-cryopreservation cell dose is 2.5 × 107 TNC/kg, and lower cell doses have been associated with poor engraftment and high nonrelapse mortality (NRM). Investigators have studied the transplantation of two cord blood units to overcome this limitation and have reported reliable engraftment and promising survival. While engraftment can be facilitated with the use of two cord blood grafts, early reports demonstrated an increased risk for acute GVHD (HR: 2–6.1). However, patients receiving double cord transplants since 2005 have experienced comparable GVHD rates to those receiving single cord blood units according to registry data.
You identify an HLA-matched, unrelated donor and plan for HCT for this patient. He asks you what conditioning regimen you intend to provide and if the choice will have an impact on his risk for GVHD.
2. Which stem cell transplant conditioning regimen is associated with the greatest risk for acute GVHD?
- Total-body irradiation (TBI)-based myeloablative conditioning
- Busulfan-based myeloablative conditioning
- Reduced-intensity conditioning
Tissue damage from the HCT conditioning regimen plays a key role in the cytokine model of acute GVHD pathophysiology. This model identifies three steps that lead to the development of GVHD. First, host tissue damage caused by the conditioning regimen activates host antigen-presenting cells (APCs). The activated host APCs then stimulate donor T-cell proliferation and differentiation. This culminates in cellular (e.g., cytotoxic T-lymphocytes and natural killer (NK) cells) and inflammatory cytokine and protein (e.g., tumor necrosis factor alpha (TNFα) and interferon gamma) effectors, causing host tissue damage and apoptosis. This model may help explain the decreased risk for GVHD observed after reduced-intensity conditioning regimens, as reported in multiple studies (relative risk (RR): 0.1–0.3). Interestingly, myeloablative doses of TBI have consistently increased the risk for GVHD above the risk from other myeloablative conditioning regimens (HR: ≥1.4), suggesting that the immunologic response to TBI-induced tissue damage differs from that to chemotherapy.
He mentions reading in a newspaper about “T-cell depletion” and that it decreases the likelihood of experiencing GVHD. He asks you about the risks associated with this strategy.
3. What posttransplant complications are associated with T-cell depletion?
- Infection
- Relapse
- Graft failure or rejection
- Posttransplant lymphoproliferative disorder (PTLD)
- All of the above
While T-cell depletion reduces the risk of acute GVHD, the lack of donor T-cells puts the patient at significant risk of other complications. All of the listed complications are sequelae of the reduced number, or absence, of T-cells. One of the first techniques used for ex vivo T-cell depletion involved two steps. Agglutination of lymphocytes with soybean lectin was followed by exposure to sheep red blood cells (which causes formation of e-rosettes of residual lymphocytes) that were subsequently removed from the stem cell product. This technique results in a 2.5- to 3-log decrease in T-cell content of the graft, which obviated the need for posttransplant GVHD prophylaxis and led to good engraftment rates and low incidence of complications. However, this method of depletion is highly operator dependent and labor intensive, and thus has not been widely adopted. Other ex vivo T-cell depletion methods include the incubation of the graft with T-cell-specific (e.g., anti-CD3) antibodies in various combinations, antithymocyte globulin or alemtuzumab (of which both may also be used for in vivo depletion), counterflow centrifugation elutriation, and column-based immunologic CD34+ cell selection. CD34+ cell collection results in a 4–5-fold decrease in T-cells and can also be safely performed without posttransplant GVHD prophylaxis; it is now the most commonly used method of ex vivo T-cell depletion due to the relative ease of this technique. Champlin et al. (2000) compared the efficacy of the different techniques (excepting CD34+ selection) through a retrospective analysis of Center for International Blood and Marrow Transplant Research (CIBMTR) data and found that, while all methods of T-cell depletion reduced the risk for acute GVHD with similar efficacy to each other, patients receiving T-cell depletion with anti-T-cell antibodies of narrow specificity had superior survival when compared to other methods (RR: 0.61–0.73, P ≤ 0.03).
The BMT Clinical Trials Network performed a phase II trial of CD34+ selected grafts from HLA-matched sibling donors for 44 patients with acute myeloid leukemia and reported 100% engraftment, 23% incidence of grade II–IV GVHD through day 100, 21% NRM, and 59% overall survival at 2 years; 11% of patients experienced lethal infections, including Epstein–Barr virus–associated PTLD. When compared to contemporaneous patients receiving T-replete HLA-matched sibling donor transplants, the investigators observed a trend toward decreased GVHD (39% vs. 23%; P = 0.07), with no difference in overall survival. A similar trial was performed using CD34+ selected unrelated donor HCT, including partially HLA-mismatched grafts, which reported 9% incidence of grade II–IV GVHD, 21% incidence of infection- or PTLD-related death, and 6% relapse incidence at 4 years. Although an uncommon complication of hematopoietic cell transplantation, the risk of PTLD is dramatically increased by T-cell depletion, with a 3–15-fold increase in RR depending on the depletion strategy.
Due to the inability to find suitably matched donors for all patients who might benefit from HCT, T-cell depletion strategies have been applied to haploidentical HCT in an attempt to expand the donor pool for patients who do not otherwise have a sufficiently matched donor. Early attempts at haploidentical HCT without T-cell depletion resulted in extremely high rates of lethal GVHD and/or graft failure. T-cell depletion of haploidentical grafts is most commonly performed by either ex vivo CD34+ cell selection or in vivo through the administration of posttransplant high-dose cyclophosphamide. T-cell depletion has significantly increased the safety of haploidentical HCT, but high rates of lethal infections, relapse, and graft rejection remain significant limitations to its wider use; these complications tend to occur at different frequencies depending on the method of T-cell depletion and the patient population. Aversa et al. (1998) reported 26% mortality due to infection at 1 year in patients receiving CD34+ cell selected haploidentical HCT for high-risk leukemia. Luznik et al. (2001) reported a 1-year relapse rate of 51% after nonmyeloablative conditioning and high-dose posttransplant cyclophosphamide for hematologic malignancy; patients with sickle cell anemia treated with a similar strategy experienced graft rejection rates of 43%.
You plan for a myeloablative conditioning regimen for this patient and now need to determine what GVHD prophylaxis strategy to use.
4. What are the common immunosuppressive strategies used for GVHD prophylaxis, how do they work, and how does one choose between strategies?
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