Steroid refractory chronic graft-versus-host disease (cGVHD) is associated with a significant morbidity and mortality. Although first-line treatment of cGVHD is based on controlled trials, second-line treatment is almost solely based on phase II trials or retrospective analyses. The consensus conference on clinical practice in cGVHD held in Regensburg aimed to achieve a consensus on the current evidence of treatment options as well as to provide guidelines for daily clinical practice. Treatment modalities are the use of steroids and calcineurin inhibitors as well as immunomodulating modalities (photopheresis, mTOR-inhibitors, thalidomide, hydroxychloroquine, vitamin A analogs, clofazimine), and cytostatic agents (mycophenolate mofetil, methotrexate, cyclophosphamide, pentostatin). Recent reports showed some efficacy of rituximab, alemtuzumab, and etanercept in selected patients. Moreover, tyrosine kinase inihibitors such as imatinib came into the field because of their ability to interfere with the platelet-derived growth factor (PDGF-R) pathway involved in fibrosis. An other treatment option is low-dose thoracoabdominal irradiation. Although different treatment options are available, the "trial-and-error system" remains the only way to identify the drug effective in the individual patient, and valid biomarkers are eagerly needed to identify the likelihood of response to a drug in advance. Moreover, the sparse evidence for most treatment entities indicates the urgent need for systematic evaluation of second-line treatment options in cGVHD.
This study evaluated azacitidine as treatment of minimal residual disease (MRD) determined by a sensitive donor chimerism analysis of CD34+ blood cells to pre-empt relapse in patients with CD34+ myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). At a median of 169 days after HSCT, 20/59 prospectively screened patients experienced a decrease of CD34+ donor chimerism to <80% and received four azacitidine cycles (75 mg/m2/day for 7 days) while in complete hematologic remission. A total of 16 patients (80%) responded with either increasing CD34+ donor chimerism to ⩾80% (n=10; 50%) or stabilization (n=6; 30%) in the absence of relapse. Stabilized patients and those with a later drop of CD34+ donor chimerism to <80% after initial response were eligible for subsequent azacitidine cycles. A total of 11 patients (55%) received a median of 4 (range, 1–11) additional cycles. Eventually, hematologic relapse occurred in 13 patients (65%), but was delayed until a median of 231 days (range, 56–558) after initial decrease of CD34+ donor chimerism to <80%. In conclusion, pre-emptive azacitidine treatment has an acceptable safety profile and can substantially prevent or delay hematologic relapse in patients with MDS or AML and MRD after allogeneic HSCT.
and cell-surface receptors that are essential for a pro- ‡ Department of Pathology ductive immune response (Rao et al., 1997). Some of Harvard Medical School and the immunosuppressive effects of CsA may depend on The Center for Blood Research its ability to induce TGF, an immunosuppressive cyto-Boston, Massachusetts 02115 kine, in diverse cells and tissues (Suthanthiran et al., 1996). CsA or FK506 are frequently used in combination with less specific immunosuppressants such as predni-The immune system is a complex network of cellular sone, azathioprine, methotrexate, and mycophenolate and humoral factors that ensures the integrity of the mofetil to achieve synergistic immunosuppressive eforganism by attacking potential pathogens. Sometimes fects (Suthanthiran et al., 1996; Gummert et al., 1999). this normally protective system overreacts and directs The main drawback of these immunosuppressive regiits forces at the organism itself. The clinical syndrome mens, however, is that they produce major toxic side of septic shock results from overactive host responses effects and therefore are rarely employed except in serito gram-negative bacterial infections and can be fatal ous clinical situations. because of an overwhelming production of proinflam-Our thesis in this review is that since NFAT is a valimatory cytokines. Transplantation of solid organs is dated target for two clinically important immunosupconfounded by the immunologic problem of graft rejecpressive drugs, interference with NFAT regulation might tion, while graft-versus-host-disease is one of the major be expected to yield additional avenues for immunosupcomplications of transplantation with allogeneic bone pression. Moreover, since NFAT is only one of many marrow or peripheral blood stem cells, severely limiting calcineurin substrates, compounds that interfere selecthe application of these potentially life-saving therapeutively with NFAT regulation might be expected to have tic options. Other examples of inappropriate immune fewer side effects than CsA and FK506. Unfortunately, responses include allergic asthma and chronic autoimthis simple premise is complicated by the existence of mune diseases such as rheumatoid arthritis. A major multiple NFAT proteins, our incomplete knowledge of challenge for clinicians is how to suppress deleterious their regulation and function in immune and nonimmune immune responses in these diverse clinical settings. cells, and our lack of information about the mechanisms The fungal metabolites cyclosporin A (CsA) and tacrolunderlying the toxic effects of CsA and FK506. imus (FK506) are among the most potent immunosup-Here we review our current understanding of these pressive drugs available today. CsA revolutionized the points. We consider what features of NFAT regulation field of organ transplantation following its discovery in might be exploited to develop selective inhibitors of 1976 (Borel et al., 1976); it was approved for clinical use NFAT, whether such drugs would be as immunosupin 1983. Tacrolimus was described soon ...
Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation is still associated with significant morbidity and mortality. First-line treatment of cGVHD is based on steroids of 1 mg/kg/day of prednisone. The role of calcineurin inhibitors remains controversial, especially in patients with low risk for mortality (normal platelets counts), whereas patients with low platelets at diagnosis and/or high risk for steroid toxicity may be treated upfront with the combination of prednisone and a calcineurin inhibitor. Additional systemic immunosuppressive agents, like thalidomide, mycophenolic acid, and azathioprine, failed to improve treatment results in the primary treatment of cGVHD and are in part associated with higher morbidity, and in the case of azathioprine, with higher mortality. Despite advances in diagnosis of cGVHD as well as supportive care, half of the patients fail to achieve a long-lasting response to first-line treatment, and infectious morbidity continues to be significant. Therefore, immunomodulatory interventions with low infectious morbidity and mortality such as photopheresis need urgent evaluation in clinical trials. Beside systemic immunosuppression, the use of topical immunosuppressive interventions may improve local response rates and may be used as the only treatment in mild localized organ manifestations of cGVHD.
Mesenchymal stem cells have been shown to mediate immunomodulatory effects. They have been used in patients with steroid-refractory acute GVHD (aGVHD), but their relevance as a therapeutic agent targeting aGVHD has still to be defined. In this case series, we report 13 patients with steroid-refractory aGVHD who received BM-derived MSC expanded in platelet lysatecontaining medium from unrelated HLA disparate donors. MSC were characterized by their morphological, phenotypical and functional properties. All tested preparations suppressed the proliferation of in vitro activated CD4 þ T cells. MSC were transfused at a median dosage of 0.9 Â 10 6 /kg (range 0.6-1.1). The median number of MSC applications was 2 (range 1-5). Only two patients (15%) responded and did not require any further escalation of immunosuppressive therapy. Eleven patients received additional salvage immunosuppressive therapy concomitant to further MSC transfusions, and after 28 days, five of them (45%) showed a response. Four patients (31%) are alive after a median follow-up of 257 days, including one patient who initially responded to MSC treatment. In our patient cohort, response to MSC transfusion was lower than in the series reported earlier. However, our experience supports the potential efficacy of MSC in the treatment of steroid-refractory aGVHD.
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