There is no consensus regarding the most effective and least toxic approach for GvHD prevention after HLA-matched alloBMT.25
The most commonly used regimens for GvHD prophylaxis consist of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus) in combination with either methotrexate, MMF, or sirolimus.26–30
However, despite the use of pharmacological GvHD prophylaxis, acute GvHD still occurs in 35–55% of BMT recipients from HLA-matched siblings, and more frequently in recipients of unrelated donor BMT.28,30–33
As importantly, the incidence of chronic GvHD is 50% or higher with most commonly used prophylaxis regimens.26–30,34,35
Patients that do not develop chronic GvHD can be withdrawn from immune suppression within 6–9 months of transplantation. These patients are considered to have developed early donor/recipient tolerance. Patients that develop acute GvHD require secondary treatment and the majority of them remain on multiagent immunosuppression beyond the first 12 months after transplantation.36
The median duration of immunosuppressive treatment in patients that develop chronic GvHD is 23 months with approximately 15% of them requiring treatment beyond 7 years.37
Thus, it can be argued that the frequency and duration of use of secondary immunosuppression should be considered when judging the efficacy of any GvHD prophylaxis regimen.38
A GvHD prophylaxis strategy that promotes tolerance induction may obviate the need for secondary immunosuppressive treatment. By avoiding the use of CNIs, such an approach may also improve immune reconstitution and optimize anti-tumor immunity.39,40
It has been proposed that CNI by disrupting the thymic architecture41
and by blocking the induction of transplantation tolerance,5
could also play a role in the development of chronic GvHD.42,43
Thus, their omission may decrease the incidence of chronic GvHD.
Based on the results with high-dose Cy as GvHD prophylaxis in mismatched alloBMT, we studied it as sole prophylaxis of GvHD after myeloablative HLA matched related or unrelated donor BMT.44••
One hundred and seventeen consecutive hematologic malignancies patients were treated on this phase I/II clinical trial; 78 patients received HLA-matched related and 39 received HLA-matched unrelated donor allografts. Transplantation conditioning comprised oral or intravenous busulfan from days -7 to -4 (target AUC 800–1400) and Cy 50 mg/kg on days -3 and -2, followed by an infusion of donor marrow obtained in a targeted collection of 4 × 108
nucleated cells/kg. No growth factors were administered. The median patient age was 50 years with 14 patients being 60 years or older. The most common diagnosis was acute myeloid leukemia (AML; n=58, or 50%), and 68/117 patients (58%) were not in remission at the time of transplantation. Sustained engraftment of donor cells occurred in 114 patients (98%), with the median time to neutrophil recovery of 23 days for recipients of related donor and 25 days for recipients of unrelated donor allografts. High-dose post-transplantation Cy was well-tolerated; the most common toxicities were transient mild renal dysfunction or elevations of serum liver enzymes, while hepatic veno-occlusive disease developed in 10 patients (9%) and was fatal in two. The cumulative incidences of grades II–IV GvHD by day 200 after transplantation were 42% and 46% among recipients of related versus unrelated donor grafts, respectively. The incidence of grades III–IV GvHD for all patients was 10%. At 2 years after transplantation, the cumulative incidences of chronic GvHD for recipients of related versus unrelated donor grafts were 9% and 11%, respectively. In a multivariable analysis, the only variable associated with an increased risk of developing moderate-severe acute GvHD was a male recipient of a female donor graft (p=.05).
These initial results were recently updated in a follow-up report on 139 consecutive patients (79 related and 60 unrelated) treated on this study.45
With a median follow-up of 26 months, the cumulative incidences of acute grades II–IV and chronic GvHD for all patients were 45% and 10%, respectively. Only 3 patients have died with refractory GvHD. We also retrospectively analyzed the use of secondary systemic immunosuppressants (SSI) in this expanded cohort. Overall, the cumulative incidence of SSI use was 45%. The median time to initiation of SSI was 42 days (range, 19–142 days) and the median duration of SSI use was 152 days (range, 13–981 days). At 6 months and 1 year after transplantation, 63% and 85% of patients were off all immunosuppressive therapy, respectively. These results extend our previous observations that post-transplantation Cy is effective single agent prophylaxis of acute GvHD with a low rate of grade III–IV GvHD and more than half of the patients never requiring additional SSI. The limited use of SSI may be responsible for the low infection rate seen in these patients.
The overall survival (OS) and event-free survival (EFS) for all patients at 1 year after transplantation were 63% and 48%, respectively, and at 2 years after transplantation were 55% and 39%, respectively, suggesting that use of high-dose Cy for GvHD prophylaxis retains the GvL effect in these high-risk patients.44
Consistent with other recent studies, EFS and OS did not differ according to the donor type. The cumulative incidence of relapse for patients transplanted in remission was 26% at two years after transplantation. Among patients with MDS or AML in remission at the time of transplantation, the 1- and 2- year EFS were 61% and 52%, respectively. The cumulative incidence of relapse for patients with AML/MDS that were in CR at the time of allografting was 28% at 2 years. AML/MDS patients who were not in CR at the time of transplantation had a worse EFS than patients in CR, but the difference was not statistically significant (p=0.26), while the presence of circulating blasts in patients with active disease was associated with significantly poorer outcome compared to patients in CR (P=0.01. ). In conclusion, high-dose post-transplantation Cy is effective as sole prophylaxis of GvHD after HLA-matched alloHSCT, and does not appear to eliminate the allogeneic GvL effect in patients with advanced hematologic malignancies.
Event-free survival in patients AML according to disease status pretransplant after myeloablative conditioning and post-transplantation Cy as sole GVHD prophylaxis
The ability to shorten the duration of post-grafting immunosupression after HLA-matched alloHSCT with high-dose, post-transplantation Cy was marked by prompt immune reconstitution and a low incidence of opportunistic infections. Among 54 patients studied consecutively, the median absolute lymphocyte counts on day 30 and 60 after transplantation were 440/μl and >700/μl, respectively. The median CD4+
T cell count on day 60 after transplantation was 119/μl. Levels of Foxp3 mRNA, the signature transcript of regulatory T cells, in the peripheral blood of patients who did not develop GvHD were significantly greater than those detected in patients who developed GvHD. These results correlated with significantly lower levels of CD4+
cells in the blood of patients who developed GvHD. A lack of GvHD also correlated with high levels of IL-1Rα and TGF-β (mRNA transcripts), whereas the development of GvHD correlated with high levels of IFN-γ, IP-10, TNF-α and IL-6.46
No patients died of CMV or invasive fungal infection. Reactivation of CMV occurred in 24% of patients, and there were only two documented case of CMV disease. The rapid recovery of CMV-specific immunity correlated with the results of in vitro ELISPOT assays. The frequency of cells secreting interferon gamma in response to stimulation with pentadecapeptides of the immunodominant CMV protein, pp65, at day 30–60 after alloHSCT did not differ from pre-transplantation specimens from CMV-seropositive donor/recipient pairs. The absence of post-transplantation Epstein–Barr virus-associated lymphoproliferative disease is another indicator of the prompt immunologic recovery seen with post-transplantation Cy.