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Characterization of graft-versus-leukemia responses in patients treated for advanced chronic lymphocytic leukemia with donor lymphocyte infusions after in vitro T-cell depleted allogeneic stem cell transplantation following reduced-intensity conditioning

Leukemia volume 21, pages 2569–2574 (2007)Cite this article

Patients with chronic lymphocytic leukemia (CLL) unresponsive to fludarabine-based chemotherapy have a poor prognosis. For these patients allogeneic stem cell transplantation (alloSCT) may be a potential curative treatment modality. Several reports have shown that alloSCT following reduced-intensity conditioning (RIC) significantly diminished treatment-related mortality (TRM) while preserving the graft-versus-leukemia (GvL) effect. However, considerable toxicity due to a high incidence of acute graft-versus-host disease (GvHD) and extensive chronic GvHD was observed.1, 2 The use of alemtuzumab (anti-CD52) to deplete for donor and recipient T cells as part of the RIC strategy effectively reduces GvHD, while the administration of alemtuzumab with the stem cell graft may also result in a profound anti-CLL effect. Once durable donor engraftment is achieved, adoptive immunotherapy with donor lymphocyte infusion (DLI) can be applied to promote and enhance the GvL effect.3, 4 We have demonstrated the feasibility of this approach and showed a reduction in both the incidence and the severity of GvHD.5

Here, we report the result of 12 patients with advanced CLL treated with in vitro T-cell-depleted RIC alloSCT followed by postponed administration of DLI. Patients with progressive CLL after conventional chemotherapy with ages between 18 and 70 years with a human leukocyte antigen (HLA)-identical sibling donor or an HLA-compatible matched unrelated donor (MUD) were eligible for this study. Patient and transplantation characteristics of the 12 enrolled patients are summarized in Table 1. The conditioning regimen consisted of fludarabine 30 mg/m2/day i.v. on days −10 to −6, busulfan 3.2 mg/kg/day i.v. on days −6 and −5 and antithymocyte globulin 10 mg/kg/day i.v. on days −4 to −1. T-cell depletion of the stem cell product was performed by incubation with 20 mg alemtuzumab for 30 min. No post-transplant GvHD prophylaxis was administered. DLI was anticipated to be administered in all patients. Patients with persistent disease or incomplete donor chimerism at 6 months after alloSCT received 5 × 106 CD3+ cells/kg. Escalating doses of CD3+ T cells were administered at 3–6 months intervals in the absence of development of GvHD if mixed chimerism or CLL persisted. The median follow-up was 21 months (range, 7–61 months). Disease response was assessed using National Cancer Institute Working Group (NCI-WG) criteria with the following additions. Complete response (CR) or partial response (PR) required complete or at least 50% clearance of CLL cells from both bone marrow (BM) and peripheral blood (PB) as detected by multicolor flow cytometry with sequential gating strategy for CD45-high/SSC-low/CD19-positive B cells to exclude for precursor normal B cells. The sensitivity of this assay was 0.1%. Patients received a median dose of 12.3 × 106 CD34+ cells/kg (range 7.9–16.5). All patients had sustained neutrophil (>0.1 × 109/l) and platelet recovery (>20 × 109/l) with a median time to engraftment of 12 days. As shown in Table 2, before administration of DLI no significant GvHD was observed. Only one patient had developed grade I acute GvHD of the skin. Of the 12 patients, one patient did not receive DLI because of infectious complications after alloSCT. The indications for DLI were mixed chimerism (n=1), mixed chimerism and persistent disease (n=7) or progressive disease (n=3). Four patients received one dose of 5 × 106 CD3+ T cells/kg, two patients received a lower dose (2.5 × 106 CD3+ T cells/kg) because of a MUD alloSCT. Four patients received two doses and one patient (patient 10) received five doses of DLI with a maximum dose of 1.5 108 T cells/kg because of refractory disease. Four patients developed acute GvHD after DLI (one grade I, two grade II and one grade IV). These four patients developed limited chronic GvHD. Two patients died of infectious causes not related to relapse. TRM at 100 days was 0%. At the end of follow-up (median 21 months), non-relapse mortality was 19%. Sequential chimerism studies of BM cells, performed 6 months after alloSCT and before the administration of DLI, showed sustained mixed chimerism with a median donor percentage of 68% (n=11 range, 1–99%). Five patients showed conversion into full-donor chimerism within 6 months after the administration of DLI, and maintained their full-donor chimerism status at the time of last assessment (see Table 2). In three patients low percentages of donor chimerism after the alloSCT and DLI were observed due to rapidly progressing disease.

Table 1 Patient and transplant characteristics
Full size table
Table 2 Clinical outcome after alloSCT and DLI
Full size table

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Acknowledgements

This work is supported by grants from Dutch Cancer foundation, the EU 6th framework program Allostem and the Landkroon fellowship.

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  1. Department of Hematology Leiden University Medical Center, Laboratory of Experimental Hematology, Leiden, The Netherlands

    M Hoogendoorn, I Jedema, R M Y Barge, S A P van Luxemburg-Heijs, F Beaumont, E W A Marijt, R Willemze & J H F Falkenburg

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Hoogendoorn, M., Jedema, I., Barge, R. et al. Characterization of graft-versus-leukemia responses in patients treated for advanced chronic lymphocytic leukemia with donor lymphocyte infusions after in vitro T-cell depleted allogeneic stem cell transplantation following reduced-intensity conditioning. Leukemia 21, 2569–2574 (2007). https://doi.org/10.1038/sj.leu.2404838

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