We have previously demonstrated that the application of CD8-depleted donor-lymphocyte infusions (DLI) is feasible after reduced-intensity conditioning and in vivo T-cell depletion by alemtuzumab. DLI overcome slow lymphocyte recovery associated with alemtuzumab-administration and improve anti-infectious immunity and reliably convert a decreasing T-cell chimerism (Meyer et al. Blood 2007 & BMT 2010).
Here we provide clinical follow up data of 117 patients with different hematological diseases and a median observation time of 1 year (range, 1–86 months) post hematopoietic stem cell transplantation (HSCT). The majority of patients either suffered from an acute leukemia / MDS (n=54), lymphoma (n=32), myeloma (n=17), or myeloproliferative neoplasms (n=12). Two patients suffered from non-malignant diseases. The median age of the patients was 56 years (range, 19–71) and none of them qualified for a conventional conditioning regimen. 50 patients had undergone previous transplantations (autologous: n=47, allogeneic: n=3). Donors were matched siblings (n=20), matched unrelated donors (n=55), or unrelated donors with a single HLA mismatch (n=42). Between days 60 and 120 after HSCT, without calcineurin-inhibitors and in the absence of graft-versus-host disease (GVHD), 1×106 CD8-depleted DLI per kg bodyweight were administered. Up to three further DLI were given in escalating doses in 60 to 90 day intervals. Following this procedure, 45 patients received at least one dose of DLI. Among those patients who did not qualify for DLI, 50 patients had primary GVHD. In 22 patients DLI were not administered for other reasons (donor unavailable, infections, relapse). In 64% of DLI induced acute GVHD, which was the major reason for withholding the next DLI-dose step. The rate of acute GVHD > grade 2 was 30%. 10% suffered from extensive chronic GVHD. The 1 and 3 year overall survival was 63% and 43%, respectively. Survival significantly differed between the DLI and the non DLI group after 3 years (63% vs. 27%, p=0.002). Since this trial was not randomized, we also compared the DLI group to only those patients who did not receive DLI for other reasons than primary GVHD and found similar results (62% vs. 28%, p=0.01). As expected, the presence of GVHD at any time was associated with a reduced relapse rate in all patients (55.8% vs 30.8%, p=0.013). Although DLI was associated with a survival benefit, the relapse rate did not differ from that of the no-DLI cohort. AML/MDS patients represented the largest group of patients included in our study (n= 48). Among these, 41 patients achieved the time point for DLI administration, 16 of them received at least one dose of prophylactic DLI. 9 patients developed GVHD after DLI application. 20 patients had primary GVHD as major cause for not receiving DLI. The survival curves differed significantly between the DLI and non DLI group after 1 and 3 years (91.7% vs. 54%, and 82.5% vs 24% p=0.004). The estimated 5 year overall survival for all AML patients was 50.4%. There was no significant difference analyzing the relapse rate (20% vs 18.8%).
In summary, the prophylactic application of CD8-depleted DLI in the absence of GVHD was associated with a survival benefit. However, we were not able to relate this benefit to a decreased relapse rate, and we assume a better control of infections. Our data strongly support a randomized trial, comparing prophylactic vs. preemptive / therapeutic DLI application in the context of T-cell depleted HSCT.
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