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B. Dholaria et al.
hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emp- tive and prophylactic use in clinical practice.
Introduction
Allogeneic hematopoietic cell transplantation (allo- HCT) remains an important therapeutic option for a wide number of both hematologic malignancies and non- hematologic disorders. With improvements in condition- ing regimens, graft-versus-host disease (GvHD) prophy- laxis and supportive care, leading to a reduced risk of transplant-related mortality, disease relapse has become the foremost cause of mortality after allo-HCT. The cumulative incidence of relapse (CIR) after allo-HCT for acute leukemia can be as high as 40-50% with only 10- 15% long-term survival in patients experiencing leukemia recurrence.1-3 Strategies aimed at preventing and/or treat- ing disease relapse have the greatest potential to improve transplant outcomes. Donor-lymphocyte infusion (DLI) has an established role in the management of disease relapse after allo-HCT. Unmanipulated DLI is a form of immunotherapy, which can induce durable remissions by enhancing the graft-versus-tumor (GvT) effect.4-6 Efficacy of DLI varies by type and burden of the disease.7 DLI is more effective in chronic myeloid leukemia (CML), lead- ing to complete remission (CR) in 70-80% of patients in hematologic or cytogenetic CML relapse, whereas less than 40% of acute leukemia patients respond to DLI.8,9 A study by Schmid et al. using the European Society for Blood and Marrow Transplantation (EBMT) registry showed DLI was associated with improved survival of patients with AML in the first hematologic relapse after allo-HCT, but 2-year overall survival (OS) was only 15% if DLI was given in the setting of active disease.10 Pre- emptive DLI for mixed chimerism or molecular disease relapse and prophylactic DLI for high-risk hematologic malignancies have also been studied with promising results in the setting of human leukocyte antigen (HLA)- matched allo-HCT.11-13
Allo-HCT from an HLA-haploidentical related donor (haplo-HCT) has emerged as a suitable alternative for those patients who need an allograft but who lack an HLA-matched related or unrelated donor.14,15 Several T- cell depleted and T-cell replete haploidentical transplant strategies are applied today. In T-cell replete haploidenti- cal stem cell transplantation, the use of post-transplant cyclophosphamide (PTCy) has rapidly increased across the globe due to its logistical simplicity and efficacy.2 Another T-cell replete haplo-HCT platform is granulocyte colony stimulating factor (GCSF)-antithymocyte globulin (ATG)-based or “GIAC” protocol’ [GCSF-stimulation of the donor; intensified immunosuppression through post- transplantation cyclosporine (CSA), mycophenolate mofetil (MMF), and short-course methotrexate (MTX); anti-thymocyte globulin (ATG); and combination of peripheral blood stem cells (PBSC) and bone marrow (BM) allografts] initially developed at the Peking University.16 Today’s T-cell depleted strategies derive
from the mega-dose CD34+ protocol developed at the Perugia University17 and represent a historical standard in T-cell depletion. From this platform, several other T-cell depleted strategies have evolved, such as CD3/CD19 cell depletion18 and α-β-T/CD19-B cell depletion.19 The adop- tive transfer of selectively allo-depleted20 or gene-modi- fied T cells with a suicide switch21,22 after T-cell depleted transplantation have further optimized this transplant form and are now being investigated in large randomized trials in comparison with PTCy.
Haplo-HCT with PTCy has shown comparable clinical outcomes to matched unrelated donor allo-HCT in retro- spective analyses with a significantly lower risk of chronic GvHD in myeloid and lymphoid malignancies, regardless of whether the graft was obtained from BM or mobilized PBSC.23-26 There is concern that DLI from a haploidentical donor (haplo-DLI) may pose an increased risk for GvHD, given the higher degree of HLA disparity between the donor and recipient. However, a greater HLA-disparity may also be beneficial in promoting a stronger GvT effect.27 Another advantage is that a related haploidentical donor is, in most cases, readily available and collection is faster than a registry-based unrelated donor. While the experience with haplo-DLI is limited, and there are many uncertainties around its clinical appli- cation, it can be a powerful tool to manage a disease relapse after haplo-HCT. Nonetheless, it should be emphasized that haplo-DLI after T-cell depleted trans- plantation without full immune reconstitution may have very different effects than after T-cell replete transplanta- tion and may require completely different dosing strate- gies. Therefore, in the absence of data from prospective clinical trials, general recommendations cannot be made.
In this review, we summarize the published experience with haplo-DLI and provide recommendations regarding its use in various clinical settings (therapeutic vs. pre- emptive vs. prophylactic DLI), use of chemotherapy before DLI, optimal cell dose, and concurrent immuno- suppression management. Newer strategies using cellu- lar engineering, donor-derived natural killer (NK) cells and pharmacological immunomodulation are also dis- cussed.
Therapeutic haplo-donor-lymphocyte infusion: hematologic relapse
Previously published retrospective studies have sug- gested that outcomes of haplo-DLI in patients with hematologic relapse are comparable to standard DLI from an HLA-matched donor. The incidence of DLI-associated GvHD also appears to be similar regardless of donor type.28-30 Possible explanations, at least when used late post transplant, are the use of lower cell dose and pres- ence of donor-derived tolerogenic cells in the recipient,
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haematologica | 2020; 105(1)