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Donor lymphocyte infusion in haplo-HCT
and OS were 25% and 63%, respectively.60 Lewalle et al. reported the outcomes of 12 patients who received pro- phylactic haplo-DLI starting on d+28 after T-/B-cell depleted haplo-HCT in a prospective study. One-year RFS, NRM, and OS were 50%, 0%, and 50%, respective- ly.65 Despite the encouraging results with prophylactic infusion of T-cell subset after a T-cell deplete/CD34+ selected haplo-HCT, its widespread adoption has been challenging as cell selection remains a labor-intensive and expensive process.
Prophylactic donor-lymphocyte infusion in T-cell replete haplo-hematopoietic cell transplantation
The Chinese group has led the way by incorporating prophylactic GBPC in high-risk malignancies after a haplo-HCT with the GCSF-ATG-based protocol. In a ret- rospective study by Wang et al., 61 patients with high-risk leukemia who underwent GBPC infusion were compared to 27 patients who received routine care after an haplo- HCT. Prophylactic GBPC was associated with lower relapse rate (36% vs. 55%; P=0.017) and superior estimat- ed 3-year survival (31% vs. 11%; P=0.001) compared to routine care. There was no difference in NRM between the two groups.66 A prospective study by the same group enrolled 62 patients with high-risk acute leukemia. All patients received prophylactic GPBC between d+45 and d+60 and further DLI were guided by MRD and GvHD status. Three-year DFS, NRM, and OS were 51%, 18%, and 49%, respectively. Acute and chronic GvHD were seen in 47% and 63% patients, respectively. Outcomes were similar between recipients of haploidentical (n=62) versus matched donor (n=38) prophylactic DLI.32
Jaiswal et al. reported their prospective experience with prophylactic GBPC in the T-cell replete haplo-HCT/PTCy setting. Twenty-one patients with AML (not in remission) received up to three doses of haplo-GPBC (d+21, d+35 and d+60). They were compared with 20 patients who received routine monitoring after haplo-HCT. At 18 months, CIR, PFS, and OS were 21% versus 66%; 62% versus 25% and 71% versus 35% in DLI and routine care cohorts, respectively. Incidence of aGvHD was 31%, while incidence of chronic GvHD was 41% after GBPC infusions. NRM was equivalent between the groups.56 Recently, Cauchios et al. reported outcomes of 36 patients who received prophylactic haplo-DLI after a haplo- HCT/PTCy. One-year PFS and OS were 76% and 83%, respectively. The cumulative incidence of relapse was 16% and the incidence of DLI-associated GvHD was 33%.67
Practical aspects of haplo-donor-lymphocyte infusion
Cell dose
The CD3+ T-cell dose ranged from 0.01 to 8.8x108 mononuclear cells/kg in reports on therapeutic DLI from a matched donor.7 A study reported a relatively lower rate of GvHD with an escalating cell dose regimen versus a sin- gle bulk infusion of DLI from HLA-matched donors. Disease responses were similar between the two approaches.68 There was no dose-response relationship with GvHD or disease response rates in haplo-DLI in the setting of T-cell depleted haplo-HCT.28,29 The average starting dose for therapeutic haplo-DLI in the T-cell
replete haplo-HCT/PTCy setting was 1 or 2 log lower than the standard DLI dose (1x107 CD3+ cells/kg) from HLA-matched donors. In a report on 40 patients, a cell dose of 1x106 CD3+ cells/kg was associated with grade 2- 4 aGvHD in 17% of patients, and a CR rate of 27%.28 Goldsmith et al. used the same dose in 21 patients; only seven (33%) developed aGvHD (grade 3-4 aGvHD in 1 patient).30 These incidences of aGvHD were lower than those reported by the Chinese group using haplo-GBPC at 1 to 2 log higher cell dose with the GCSF-ATG-based protocol. A starting cell dose of 1x107 to 1x108 CD3+ cells/kg was associated with grade 2-4 aGvHD in 50-60% (grade 3-4 aGvHD approximately 30%) of patients.31,38,69 Subsequent reports by Yan et al. showed a reduced inci- dence of aGvHD with the routine use of short-term GvHD prophylaxis after GBPC infusion.39 Available data suggest that 1x106 CD3+cells/kg is a reasonable starting dose with appropriate repeated dose escalation every 4-6 weeks based on disease response and GvHD for thera- peutic haplo-DLI in T-replete haplo-HCT with PTCy. Clinical trials are needed to establish the optimal timing and cell dose in prophylactic and T-cell depleted haplo- HCT settings. Published studies have used wide-ranging repeated non-escalating cell doses for pre-emptive or pro- phylactic DLI.32,37,54
The end point of donor-lymphocyte infusion therapy
It is important to establish the goal of DLI therapy beforehand as each DLI is associated with increased risk of GvHD. Patients with DLI-responsive relapse usually respond within 2-3 months.7 Repeated infusions of esca- lating doses of therapeutic DLI can be administered until CR is achieved (ideally an MRD-negative status) or the patient develops clinically significant GvHD. Patients should be evaluated for GvHD, donor chimerism and dis- ease response after each DLI. Pre-emptive DLI for MRD persistence after allo-HCT may be stopped once the achievement of MRD negativity, significant GvHD or a hematologic relapse occurs. Donor chimerism should be assessed after each pre-emptive DLI for MC. Pre-emptive DLI may be stopped once ≥90% donor chimerism is achieved. As noted above, DLI can result in marrow apla- sia in those patients who have converted to host chimerism. There is no standard duration of prophylactic DLI outside a clinical trial. In these circumstances, each dose of prophylactic haplo-DLI should be used with cau- tion, balancing the risk of disease relapse and GvHD.
Traditional donor-lymphocyte infusion versus granulocyte colony-stimulating factor-primed peripheral blood progenitor cell infusion
Standard DLI uses freshly collected unmanipulated donor lymphocytes. This approach privileges tumor alloreactivity over the risk of GvHD. GCSF promotes T- cell hypo-responsiveness in marrow grafts by increasing the number of plasmacytoid dendritic cells and mono- cytes. It also reduces the expression of co-stimulatory CD28/B7 on monocytes, B and T cells,70 promotes macrophage71 and T-cell polarization in the BM graft towards the more tolerogenic pattern. This property is maintained even after in vitro mixture of G-CSF primed BM and PBSC grafts.72,73 The Chinese group has reported their extensive experience with using GBPC instead of unmanipulated DLI. Huang et al. reported the outcomes of 20 patients who received therapeutic GBPC from hap-
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