Donor Lymphocyte Infusion

Donor lymphocyte infusion to treat relapse after allogeneic bone marrow transplantation for myelodysplastic syndrome

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Summary:

Donor lymphocyte infusion has become established as a salvage therapy for patients with hematological disorders relapsing after allogeneic bone marrow transplantation (BMT). The role of donor lymphocyte infusion for patients with myelodysplastic syndrome (MDS) remains to be established. Between July 1993 and October 2001, 14 patients with MDS relapsing after allogeneic BMT received DLI as salvage therapy. At the time of BMT, one patient had RA, nine had RAEB, of whom three were in CR after induction-type chemotherapy, two had RAEB-T, one had CMML and one had AML. Donors were HLA-matched siblings (n=12), HLA-matched other relative (n=1) and unrelated (n=1). At the time of relapse, the median marrow blast count was 9%. The median CD3+ cell dose administered was 6.3 × 107/kg. With a median follow-up of 49 months, six patients were alive, of whom two were in CR after DLI alone and remained disease-free, two were in CR after a second BMT and two had active disease. Eight patients died of disease progression. Although DLI alone seems to be effective in a small number of patients with MDS, other treatment strategies, including prior debulking chemotherapy, deserve investigation.

Main

Myelodysplastic syndromes (MDS) are defined as clonal malignant hematopoietic disorders for which treatment remains disappointing. Although variable success has been obtained with conventional treatments such as differentiating agents, hematopietic growth factors or intensive chemotherapy, these treatments do not seem to have any effect on disease progression and survival.1,2,3,4 For younger patients having an HLA-matched donor, allogeneic bone marrow transplantation (BMT) provides the only potentially curative treatment with approximately 40% of treated individuals becoming long-term disease-free survivors.5,6,7,8

Relapse after allogeneic BMT remains one of the major causes of treatment failure, and is responsible for about 50% of deaths. Only a minority of relapsed patients is cured with a second BMT, which itself results in significant morbidity and mortality.9,10,11 Adoptive immunotherapy with donor lymphocyte infusion (DLI) has become established as a salvage therapy for patients with hematological disorders relapsing after allogeneic BMT.12,13,14,15 Few studies, however, have addressed the effect of such treatment in MDS.16,17,18,19 We report the results of DLI in 14 patients in five SFGM-TC centers with MDS in relapse after allogeneic BMT.

Patients and methods

Patients and transplantation modalities

Between July 1993 and October 2001, 14 patients with MDS in relapse following allogeneic BMT received DLI as salvage therapy. Participating centers were asked to verify the data referred to the French Bone Marrow Registry, and to provide additional information on each patient. The initial patient characteristics are described in Table 1. According to the French–American–British (FAB) classification,20 two patients had refractory anemia (RA) at diagnosis, of whom one had progressed to refractory anemia with excess blasts (RAEB) before BMT. In all, 10 patients had RAEB at diagnosis, of whom one had progressed to RAEB in transformation (RAEB-T) and one to acute myeloid leukemia (AML) before BMT. One patient had RAEB-T and one had chronic myelomonocytic leukemia (CMML). Three of the four patients with RAEB, who received induction-type chemotherapy, were in CR at the time of BMT. Cytogenetic evaluation was available for 13 patients, of whom seven had a normal karyotype, three had trisomy 8, one had a complex karyotype, one had monosomy 7 and one had a chromosome 3 abnormality. The median time from diagnosis to BMT was 7 months (range 1.7–14.7) and the median age at BMT was 46.5 years (range 32.5–61.8). Donors were HLA-matched siblings (n=12), HLA-matched other relative (n=1) and HLA-matched but unrelated (n=1). A total of 11 patients received myeloablative conditioning regimens and three received nonmyeloablative conditioning regimens. Graft-versus-host disease (GVHD) prophylaxis was based on cyclosporine-A with methotrexate (n=13) or cyclosporine-A alone (n=1). Acute and chronic GVHD were scored according to standard criteria.21 Relapse was defined as the presence of >5% marrow blasts and/or reappearance of cytopenia with major myelodysplastic features associated with evidence of autologous reconstitution when chimerism was available.

Table 1 Initial characteristics of the 14 allografted patients for MDS

Results

Engraftment and transplantation toxicity

All patients experienced neutrophil engraftment. However, three of them never reached a platelet count of 50 × 109/l. The median time to reach a neutrophil count of 0.5 × 109/l was 20 days (range 14–33 days) and the estimated median time to reach a platelet count of 50 × 109/l was 27 days (range 18 – not reached) after BMT.

Seven patients developed acute GVHD, including two with grade-III disease. Three patients developed chronic GVHD, including one with extensive disease. Immediate post BMT (within 3 months after BMT) chimerism was available for 11 patients, of whom four had a total donor profile and seven had partial chimerism.

Relapse

The median time from BMT to relapse was 319 days (range 93–1731 days). Patient characteristics at the time of relapse are summarized in Table 2. At the time of relapse, the median percentage of marrow blasts was 9% (range 2–41%). Chimerism was partial in the 11 patients assessed. The median time from relapse to DLI was 35 days (range 3–805).The median number of DLI was 2.5 infusions/patient (range 1–5). The median total cell dose injected was 6.3 × 107 CD3+/kg of the recipient body weight (range 1–28.7 × 107). Two patients received intensive chemotherapy (CT) before DLI, but one of them (no. 1) failed to achieve CR. The other patient (no. 3) achieved CR initially, but then received DLI 805 days later after a second relapse associated with 85% marrow blasts. He failed to enter into CR with DLI alone, but thereafter received additional induction-type chemotherapy and underwent a second allogeneic minitransplant after achieving a subsequent CR. He is currently alive 1339+ days after DLI. Patient no. 14 received Danazol and started to improve his hematopoiesis before DLI. Danazol was discontinued 3 months after DLI and he is alive, and in CR with total donor chimerism 727+ days after DLI.

Table 2 Patient characteristics at the time of relapse, DLI modalities and outcome

Patients' outcome

At the reference date of October 15, 2003, the median follow-up after DLI was 49 months (range 24–123) and six patients were alive, of whom two (nos. 7 and 14) were in CR after DLI and remained disease-free +1845 and +727 days after DLI. Two other patients (nos. 2 and 3) re-entered CR after a second BMT, and remained alive +2862 and +1339 days after DLI. The remaining two patients (nos. 5 and 13) were still alive, with active disease +971 and +1028 days after DLI.

Eight patients died of disease progression 35–694 days after DLI. No patient died of transplant-related mortality (TRM). The estimated overall survival from the time of DLI was 528 days. None of the following variables influenced survival: age, gender, FAB classification at BMT, GVHD before DLI, chimerism, percentage of marrow blasts at relapse, DLI number or cell dose, GVHD after DLI. This is probably due to the small number of patients in our study.

DLI-induced GVHD was recorded in seven patients as follows: Six patients developed grade-II disease, of whom one developed limited chronic GVHD and one developed a grade-III acute GVHD followed by extensive chronic GVHD. The evaluation of cytopenias after DLI was difficult, because patients already had relapse-related cytopenias. No patients received donor peripheral stem cell boosts.

Discussion

The role of the DLI-induced GVL reaction appears well established for patients with chronic myelogenous leukemia, who relapse after allogeneic BMT.22,23 Less significantly, GVL also appears to contribute to the cure of patients with AML or MDS. Shiobara et al19 reported the results of DLI in patients with relapsed CML, AML and MDS after BMT. They observed that remissions were sustainable in CML patients, whereas remissions in those with MDS and AML were transient, except in two patients with AML who received DLI at the time of molecular relapse. Recently, in a series of 452 patients allografted for MDS, Sierra et al24 observed that T-cell depletion was associated with an increased relapse rate compared with transplantation using unmanipulated marrow cells. Furthermore, in a retrospective comparison of BM and peripheral blood (PB) progenitor cells for allogeneic stem cell transplantation in MDS, Guardiola et al25 reported that the 2-year treatment failure incidence was significantly decreased in the PB group compared with the BM group. Moreover, they observed that the protective effect in the PB stem cell group was more marked in patients receiving an unmanipulated graft than in those having a T-cell-depleted graft.

The low response rate observed in our study could be explained, in part, by the high tumor burden at the time of relapse (the marrow blasts ranged from 2 to 41%). As shown in Table 2, two of our patients received induction-type chemotherapy before DLI, but one of them (no. 1) failed to achieve CR and the second (no. 3) received DLI only after a subsequent relapse. Although the value of cytoreductive chemotherapy before BMT remains to be established, the role of such treatment before DLI is probably more important, given the lack of a conditioning regimen. In a study of 12 patients with high-risk MDS who underwent reduced-intensity conditioning BMT, Kroger et al26 reported a 2-year disease-free survival (DFS) and overall survivals of 12 and 26%, respectively. In another study comparing reduced-intensity and standard conditioning regimens in patients with MDS, Parker et al27 observed a higher incidence of relapse in the reduced-intensity group (17%), and suggested that this might reflect the proportionately higher numbers of patients in the reduced-intensity arm with progressive or refractory disease at the time of transplantation. The failure of DLI-induced CR in our patient (no. 3) was probably due to the high tumor burden at DLI (85% of marrow blasts), while the CR obtained before the second minitransplant, which was done with a graft from the same donor, probably contributed to the success of the BMT in achieving the sustained CR.

This study shows that DLI is well tolerated and seems to be effective in a small number of patients. However, DLI alone should not be considered as standard treatment for remission induction in patients relapsing after allogeneic BMT for MDS, and new approaches, including prior debulking chemotherapy, need to be evaluated and might further improve the results.

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Correspondence to I Yakoub-Agha.

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Depil, S., Deconinck, E., Milpied, N. et al. Donor lymphocyte infusion to treat relapse after allogeneic bone marrow transplantation for myelodysplastic syndrome. Bone Marrow Transplant 33, 531–534 (2004) doi:10.1038/sj.bmt.1704381

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Keywords

  • myelodysplastic syndromes
  • relapse
  • allogeneic bone marrow transplantation
  • DLI

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