Page 65 - 2020_01-Haematologica-web

Donor lymphocyte infusion in haplo-HCT
patients who are at high-risk of subsequent relapses. Mo et al. reported that patients with persistent MRD after DLI had increased relapse risk (P=0.001), resulting in poor DFS (P=0.004).36 In a prospective study of 47 patients (66% received haplo-HCT), MRD-guided repeated administra- tion of pre-emptive chemo-DLI was effective in reducing the risk of subsequent relapse after achieving initial dis- ease response. The one-year CIR, DFS, and OS were 22%, 71%, and 78%, respectively (Figure 1).57
Future directions
Donor-derived natural killer cells
Natural killer cells may play a role in tumor alloreactiv- ity in the setting of mismatched or haploidentical trans- plant. A recent study showed a marked reduction in donor-derived NK cells in the recipients of PTCy, leading to blunting of NK-cell alloreactivity.89 In a pilot study, pro- phylactic infusion of CD56+/CD3+ cells after haplo- HCT/PTCy in patients with refractory active disease was safe and associated with rapid immune reconstitution.55 The same group used prophylactic DLI primed with abat- acept (CTLA4Ig), which selectively suppresses T-cell alloreactivity without interfering with NK-cell activation. Abatacept with DLI was associated with reduced inci- dence of aGvHD (10% vs. 31%) and improved relapse- free survival compared to prophylactic DLI alone.90 In a phase I study by Ciurea et al., donor-derived NK cells expanded ex vivo were infused prophylactically before and after haplo-HCT in high-risk myeloid malignancies. The intervention was safe and associated with improved NK-cell number and function, lower viral infections, and low relapse rate when compared to a historical control group.91 Several methods to enhance NK-cell alloreactivi- ty, including combination with immunomodulatory drugs,92 use of cytokine-activated NK cells,93 and selection of alloreactive single KIR+ NK cells,94 are under investiga- tion.
Engineered donor-lymphocyte infusion
Different strategies are being explored to modify DLI composition and reduce the risk of GvHD while main- taining antitumor activity. ATIR101© is a haplo-DLI prod- uct with alloreactive T cells depleted by ex vivo photode- pletion.20 In a pooled analysis of two prospective trials, 37 patients received prophylactic ATIR101© after T-cell depleted haplo-HCT. One-year relapse rate, NRM and OS were 8%, 33% and 58%, respectively. Interestingly, aGvHD (grade 3-4) and severe cGvHD were seen in 5% and 0% of the patients, respectively.95 Alloanergized DLI generated ex vivo was infused on d+35 after a CD34+ selected haplo-HCT in a phase I study. These donor lym- phocytes with the reduced donor-specific alloreactivity expanded in vivo and contributed to immune reconstitu- tion.96 Another strategy is to insert an inducible suicide gene in donor lymphocytes so that they can be selectively eliminated to treat DLI-associated GvHD.21,97 A recent analysis on 100 children with acute leukemia given a titrated number of donor T cells transduced with the inducible caspase-9 safety switch after haplo-HSCT showed an 82% probability of relapse-free survival.98
Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a potent form of adoptive cellular therapy. Two CD19 CAR-T-cell therapies have been approved by
the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for relapsed/refracto- ry high-grade B-cell lymphoma and B-ALL.99,100 Prophylactic infusion of CD19 CAR-T cells from a hap- loidentical donor was found to be safe with only mild aGvHD in one report.101 There are reports of therapeutic or pre-emptive donor-derived CAR-T-cell infusion with a small number of patients achieving durable remissions. CAR-T-cell-associated GvHD appears to be rare and of mild severity.102 Selective depletion of CD3+ αβ-TCR+ T cells (thought to be the principal mediators of GvHD) to enrich DLI with CD3+ γδ-TCR+ T cells and CD3− CD56+ NK cells is also an attractive strategy to reduce the risk of GvHD while maintaining tumor alloreactivity.103 Maschan et al. infused low-dose (1x105 CD3+cells/kg) CD45RA-depleted DLI (memory T cell) in 25 patients after TCR α/β-depleted haplo-HCT. The intervention was safe and associated with the expansion of cytomegalovirus-specific T cells in the recipients.52
Donor-lymphocyte infusion with immunomodulatory drugs
Immunomodulation with checkpoint inhibitors and targeted agents may enhance the efficacy of DLI. This may allow lower CD3+ cell dose while maintaining tumor alloreactivity. Blinatumomab (a CD19-CD3 bispecific T- cell engager) has been used with DLI for relapsed B-ALL. In a recent report of 14 patients, it appears to be safe with high response rates.104 In a prospective phase II study, DLI was administered with azacitidine and lenalidomide in patients with molecular or hematologic relapse of myeloid malignancies. The combination was relatively safe and the CR rates were 67% in MRD and 43% in hematologic relapse.80 Interferon-γ (IFNγ) induced re- expression of epigenetically silenced MHC class II anti- gens in relapsed AML clones after allo-HCT.105 One could hypothesize that treating a patient with IFNγ before haplo-DLI may result in better tumor alloreactivity, although it may also increase the risk of GvHD.
Conclusions
• Unmanipulated DLI from a haploidentical donor appears to be relatively safe and reasonably effective in patients who relapse after a T-cell replete haplo-HCT. Patients given haplo-DLI should be enrolled in a clinical trial whenever possible, as data regarding optimal cell dose, timing and role of concurrent systemic therapies with haplo-DLI are limited. Information about the appli- cation of unmanipulated DLI after T-cell depleted trans- plantation is limited, which is why dosing should be managed with caution.
• The risk of GvHD after unmanipulated DLI in the haplo-HCT/PTCy setting is comparable to an unmanipu- lated DLI from an HLA-matched donor.
• Cytoreductive therapy prior to DLI from a haploiden- tical donor should be considered in patients with a hema- tologic relapse after haplo-HCT.
• Pre-emptive haplo-DLI may play a role in reducing disease relapse in patients with persistent MRD or mixed- donor chimerism after haplo-HCT; however, more stud- ies are needed.
• Patients with high-risk myeloid malignancies may benefit from a prophylactic haplo-DLI, which should ide-
haematologica | 2020; 105(1)
55