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Donor lymphocyte infusion in haplo-HCT
which may reduce their alloreactivity and, thus, the risk of GvHD. The type of haplo-HCT protocol may influ- ence outcomes of subsequent haplo-DLI. The current therapeutic haplo-DLI experience is limited to haplo- HCT/PTCy or a ‘GCSF-ATG-based protocol’. Table 1 summarizes the published studies using DLI from a hap- loidentical donor.
Therapeutic donor-lymphocyte infusion in T-cell replete haplo-hematopoietic cell transplantation
Zeidan et al. retrospectively reported results of haplo- DLI in 40 patients [minimal residual disease (MRD)/loss of chimerism (LOC): n=5; hematologic relapse: n=35] after a haplo-HCT/PTCy with BM graft. At the median follow up of seven months, CR was achieved in 30% of patients (CR after a hematologic relapse: 26%) and acute GvHD (aGvHD) occurred in 25% of them. At time of last follow up, six patients were alive in CR for over a year after the intervention. The cell dose in most DLI was 1x106 CD3+ cells/kg and the majority of patients received cytoreductive chemotherapy before DLI.28 Subsequently, two similar reports showed that haplo-DLI after chemotherapy successfully resulted in CR in approxi- mately 30% of the patients with a subset of long-term survivors.29,30 The incidence of grade 2-4 aGvHD was approximately 30%, and only 5% of patients developed grade 3-4 aGvHD. No patient (0%) developed extensive chronic GvHD (cGvHD).29,30 None of these studies used immunosuppression for GvHD prophylaxis after haplo- DLI. Disease responses and GvHD rates were comparable between patients who received BM versus a PBSC graft.30 Patients with relapsed Hodgkin lymphoma appear to have relatively better disease responses to haplo-DLI compared to those with acute leukemia (40% vs. 33%).29 In a smaller retrospective study (n=21) published by Goldsmith et al., the authors showed that patients with extra-medullary disease relapse had a better relapse-free survival (RFS) compared to those with marrow relapse (4- month RFS 43% vs. 8%).30 The group at Peking University has developed a haplo-DLI protocol using GCSF-primed peripheral blood progenitor cells (GBPC) with short-term immunosuppression. They have used a higher cell dose (1x107 to 1x108 CD3+ cells/kg) than that used in haplo-DLI in the setting of allo-HCT/PTCy (1x105 to 1x106 CD3+ cells/kg).31-37 An earlier prospective study using GBPC without immunosuppression resulted in a high incidence of severe GvHD (grade 3-4 aGvHD 30%, extensive cGvHD 30%), resulting in 2-year disease-free survival (DFS) of 40% and non-relapse mortality (NRM) of 25%.38 Subsequent studies used cytoreductive chemotherapy before GBPC infusion (chemo-DLI) followed by GvHD prophylaxis with low-dose weekly MTX or CSA for 6-8 weeks. A retrospective report by Yan et al. on 55 patients with relapsed acute leukemia showed 3-year DFS, NRM, and OS of 24%,13%, and 25%, respectively. A total of 76% of patients achieved CR (MRD negative CR: 55%).39 Relapse after achieving CR following chemo-DLI was a major problem, resulting in poor long-term survival. In spite of the limitations of cross-study comparison, out- comes of chemo-GBPC infusion with short-course immunosuppression are comparable to unmanipulated haplo-DLI after haplo-HCT/PTCy.
Pre-emptive haplo-donor-lymphocyte infusion: minimal residual disease, mixed-donor chimerism
Impact of minimal residual disease and mixed- chimerism on haplo-hematopoietic cell transplantation outcomes
Strategies are being explored to reliably predict the risk of disease relapse after an allo-HCT in the hope of imple- menting pre-emptive treatments. The presence of MRD before or after allo-HCT is associated with significantly increased risk of relapse and reduced survival in both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).40,41 Canaani et al. looked at pre-haplo- HCT MRD positivity in AML patients and showed its negative correlation with leukemia-free survival.42 Low donor T-cell chimerism [mixed-chimerism (MC)] after an allo-HCT is also associated with poor donor-derived immune reconstitution and increased risk of disease relapse, especially after myeloablative conditioning. In patients with AML/MDS who underwent myeloablative allo-HCT, donor T-cell chimerism <85% at day (d)+90 and d+120 was associated with increased risk of 3-year disease progression (HR=2.1, P=0.04).43 Koreth et al. reported that d+100 total donor chimerism <90% was associated with increased risk of relapse (HR= 2.54, P<0.001) and lower OS (HR=1.50, P=0.009) in patients after a reduced-intensity allo-HCT.44 Pre-emptive DLI from a full matched donor for MRD and MC appears to be safe and effective in improving disease-specific out- comes.45,46
Pre-emptive donor-lymphocyte infusion in T-cell replete haplo-hematopoietic cell transplantation
In the previously mentioned retrospective study by Zeidan et al., 3 of 4 patients who received haplo-DLI for MRD entered CR.28 Similarly, other reports showed high- er response rates in patients who received haplo-DLI for MRD or MC compared to the administration at the time of hematologic relapse.29,30 Yan et al. reported comparative outcomes of prospective studies of standard-risk acute leukemia and MDS patients with persistent MRD after allo-HCT (haploidentical donor, n=29; matched donor, n=27), who received low-dose interleukin-2 (IL-2) or pre- emptive DLI. The latter was associated with reduced 3- year CIR compared to IL-2 alone (28% vs. 64%; P=0.001).31 In another retrospective study by Mo et al., 101 patients (haplo-HCT, n=56) received chemo-DLI for persistent MRD after an allo-HCT. Three-year CIR, NRM, and OS were 40%, 10%, and 52%, respectively. Patients who cleared their MRD within 30 days after pre- emptive chemo-DLI had lower relapse rates compared to those with persistent MRD beyond 30 days (20% vs. 47%; P=0.001).36 It should be noted that the published data on pre-emptive haplo-DLI for MC is limited to a few patients28,30 and further studies are needed to establish its role in preventing disease relapse.
It is important to monitor for MRD after allo-HCT as DLI is probably more effective when administered for MRD only compared overt hematologic relapse.47 Retrospective studies have shown that persistent MRD post-transplant is associated with high relapse rate and poor outcomes,48 and the eradication of MRD improves survival.46 Comparative studies are needed between DLI and other systemic therapies in order to develop disease-
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