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B. Dholaria et al.
loidentical donors (the majority of whom received sal- vage therapy prior to GBPC infusion); CR was achieved in 75% of patients and the rates of acute and chronic GvHD were 55% and 64%, respectively.38 In another study of pre-emptive GBPC infusion for MRD after an allo-HCT (haploidentical related donor: n=29; matched- related donor: n=26), the incidences of acute and chronic GvHD were 31% and 43%, respectively. Routine debulking chemotherapy and short-term immunosup- pression were used in most studies using GBPC.31 A prospective observational study by Jaiswal et al. used prophylactic-GBPC in the setting of T-cell replete haplo- HCT/PTCy.56 The incidence of aGvHD was comparable but cGvHD was higher than that reported with unma- nipulated haplo-DLI in the PTCy setting.28-30 A recent report from Mexico showed that administration of G- CSF-primed whole blood units (median cell count 6.7x106 CD3+ cells/kg) from haploidentical donors is safe, with disease responses and improvement in MC in a subset of patients.74 Whole blood units can potentially reduce the cost associated with haplo-DLI in developing countries. Long-term immune tolerance after PTCy may be enough to overcome the immunological barrier of haplo-DLI, and GCSF priming may not be required in this setting. Comparative studies between unmanipulat- ed DLI versus GBPC in the setting of haplo-HCT/PTCy are needed.
Role of concurrent immunosuppression
Graft-versus-host disease is the main limiting toxicity of DLI, and short-term immunosuppression with DLI may improve the safety of DLI. Yan et al. reported aGvHD in 31% of patients after pre-emptive GBPC infusion for MRD persistence after T-cell replete haplo-HCT.31 All patients received CSA or low-dose MTX for 6-8 weeks after GBPC. There was no difference in acute and chronic GvHD rates between CSA and MTX. MTX was associat- ed with lower relapse rate (38% vs. 81%; P=0.029) and better DFS (52% vs. 16%; P=0.06). Patients who received MTX had higher absolute lymphocyte count compared to those who received CSA, which may have contributed to better GvT effect.39 The same group also showed that patients receiving GvHD prophylaxis for 6-8 weeks had a lower cumulative incidence of grade 3-4 aGvHD than patients receiving prophylaxis for 4-6, 2-4, and <2 weeks (9%, 14%, 32%, and 50%, respectively; P=0.018).69 In a retrospective study, Mo et al. used pre-emptive chemo- DLI for MRD persistence along with routine prophylaxis with CSA or MTX (haploidentical donor 6-8 weeks; matched donor 4-6 weeks). The incidence of aGvHD was only 9% (grade 3-4 aGvHD: 4%) in their cohort of 101 patients.36 It is important to note here that haplo-DLI without concurrent immunosuppression in the T-cell replete haplo-HCT/PTCy setting has been reported to have a similar incidence of GvHD compared to the GCSF- ATG-based haplo-HCT protocol, which routinely uses prophylactic immunosuppression with DLI.28 The poten- tial impairment of the DLI-mediated GvT effect by CSA or MTX is a concern when managing a hematologic relapse. It is reasonable to add short-term MTX after a pre-emptive or prophylactic haplo-DLI, especially in patients with a history of GvHD.56 There are no data available on concurrent immunosuppression with thera- peutic haplo-DLI in the T-cell replete haplo-HCT/PTCy setting.
Combination of systemic therapies with donor-lymphocyte infusion
Administration of salvage therapy before the infusion of DLI may improve its efficacy by reducing the tumor burden and supporting in vivo expansion of infused T cells. In this regard, chemotherapy helps eliminate regula- tory donor T cells and create a favorable immunological environment for DLI by increasing serum levels of IL-7 that favors peripheral expansion of T cells.75 In the retro- spective study by Zeidan et al., patients who received a cytoreductive therapy had better CR rates compared to those who received unmanipulated haplo-DLI without any preceding therapy (39% vs. 8%).28 This beneficial effect of pre-DLI chemotherapy was not seen in a similar report by Goldsmith et al.30
The downside of pre-DLI chemotherapy is tissue injury and inflammatory cytokine surge which may increase the risk of GvHD, especially when used closer to the allo- HCT.76 Intensive chemotherapy after an allo-HCT is poor- ly tolerated, and infectious complications are common.34,76 Recently, hypomethylating agents (i.e. azacitidine, decitabine) have been used with DLI for relapsed AML/MDS. Azacitidine can induce allogeneic CD8+ T- cell response by enhancing the expression of epigenetical- ly silenced tumor-associated antigens.77 A combination of a hypomethylating agent and DLI is safe with no appar- ent increase in GvHD or infection risk compared to DLI- alone.78,79 In a prospective study using azacitidine with DLI for relapsed disease after HLA-matched allo-HCT, the CR rate was 23% and the 2-year OS was 17%.80 Another retrospective study utilizing decitabine followed by DLI for relapsed myeloid malignancies showed an overall response rate of 25% with 2-year OS of 11%.81 Drugs targeting specific molecular anomalies (BCR-ABL1, FLT3-ITD, IDH1, IDH2) are increasingly being incorporat- ed in the treatment of disease relapse or as maintenance therapy after allo-HCT.82,83 These drugs are safer com- pared to traditional salvage chemotherapy and may pro- vide benefit when administered in combination with DLI.84
Immune escape after haplo-hematopoietic cell transplantation
Recent data have shed light on mechanisms of immune escape causing disease relapse after haplo-HCT. In haplo- SCT, HLA haplotype mismatched in the donor/recipient pair was replaced by a shared parent haplotype (uni- parental disomy) in 5 of 17 patients with relapsed AML post-haplo-HCT.85 In a subsequent retrospective analysis of 69 patients who relapsed after haplo-HCT, mis- matched-HLA haplotype loss accounted for 33% of the relapses.86 Based on retrospective studies, a second allo- HCT using a donor with a different mismatched haplo- type or a mismatched unrelated donor may induce a bet- ter GvT effect compared to same donor from the first haplo-HCT.86,87 At present, there is no standardized method of detecting loss of mismatched HLA haplotype in leukemic cells. HLA-allele specific quantitative poly- merase chain reaction is required to quantify recipient- and donor-specific alleles to confirm uniparental disomy in low-burden disease relapse.86,88
Historically speaking, most patients receiving therapeu- tic DLI relapse and succumb to their disease. Close mon- itoring of MRD and donor chimerism after a successful therapeutic haplo-DLI is important to identify the
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haematologica | 2020; 105(1)