Skip to main content
NCBI home page
Nature Portfolio logoLink to Nature Portfolio
. 2024 Aug 12;59(11):1513–1524. doi: 10.1038/s41409-024-02312-4

Safety but limited efficacy of donor lymphocyte infusion for post-transplantation cyclophosphamide-treated patients

Krithika Shanmugasundaram 1, Scott Napier 1,#, Dimana Dimitrova 1,#, Anita Stokes 1, Jennifer Wilder 2, Amy Chai 1, Andrea Lisco 3, Megan V Anderson 3, Irini Sereti 3, Gulbu Uzel 4, Alexandra F Freeman 4, Christi McKeown 1, Jennifer Sponaugle 1, Ruby Sabina 1, Kamil Rechache 1, Mustafa A Hyder 1, Jennifer A Kanakry 1,✉, Christopher G Kanakry 1,✉
PMCID: PMC11530367  PMID: 39134710

Abstract

The therapeutic efficacy of donor lymphocyte infusions (DLIs) given after allogeneic hematopoietic cell transplantation (HCT) is limited by risk of graft-versus-host disease (GVHD). Post-transplantation cyclophosphamide (PTCy) effectively prevents severe GVHD, but there are limited data on outcomes of DLIs given to PTCy-treated patients. We reviewed 162 consecutive PTCy-treated patients transplanted between 2015–2022 within the Center for Immuno-Oncology at the National Cancer Institute. Of 38 DLIs given to 21 patients after 22 HCTs, few DLIs were associated with toxicities of acute GVHD (7.8%), cytokine release syndrome (CRS, 7.8%), or chronic GVHD (2.6%), and all occurred in those receiving serotherapy-containing pre-HCT conditioning (50% of HCTs). Seven DLIs resulted in complete response (18.4%), with 5 of these given after HCTs using serotherapy-containing conditioning. Excluding infectious indications, complete response to DLIs given after transplants with versus without serotherapy-containing pre-HCT conditioning were 30% and 4.3%, respectively. Two patients received DLI for infection and experienced complete resolution without GVHD or CRS, although the efficacy cannot be definitively attributable to the DLI. DLIs given to PTCy-treated patients had low toxicity but limited efficacy, although pre-HCT serotherapy may modulate both toxicity and response. Novel strategies are needed to enhance the therapeutic efficacy of post-transplant cellular therapies without aggravating GVHD.

Subject terms: Cancer immunotherapy, Haematological cancer

Introduction

Malignancy relapse remains the leading cause for failure of allogeneic hematopoietic cell transplantation (HCT) [1]. Donor lymphocyte infusions (DLIs) remain a major strategy to treat and prevent post-transplant relapse, with the highest response rate seen in chronic-phase chronic myelogenous leukemia (CML) (60–78%) [2–6]. Long-term responses also are seen in a minority of patients with blast-phase CML (17%) or acute myeloid leukemia (AML) (14–37%), but are very low in acute lymphoblastic leukemia (ALL) (<16%) or non-Hodgkin lymphoma (<10%) [3, 4, 7, 8, 9]. DLIs also are commonly used to treat mixed chimerism and sometimes are used to treat post-transplant infections [6, 10]. Nevertheless, even with limited response, risk for graft-versus-host disease (GVHD) after DLI is quite high with incidences ranging from 41–60% [3, 4, 7, 8, 9]. Chance of response is improved when disease-targeted, lymphodepleting therapy is given prior to DLI, although toxicity of treatment including risk of GVHD is exacerbated [9, 11–14].

Post-transplantation cyclophosphamide (PTCy) has had a marked impact on the field of allogeneic HCT by reducing the risks of severe acute and chronic GVHD, in part by facilitating rapid recovery of regulatory T cells (Tregs) [15–19]. Moreover, preclinical data from our group have shown that PTCy rapidly induces suppressive mechanisms within 24 h that are sufficient to prevent GVHD induction by subsequent donor T-cell infusions [15, 17], with this effect dependent on Foxp3+ Tregs. [20] Indeed, other groups have found that the risk for GVHD from DLI in PTCy-treated patients appears more modest than that seen with conventional calcineurin-inhibitor-based GVHD prophylaxis [3, 9, 12, 13, 21–24] even when using HLA-partially-mismatched donors.

These preclinical and clinical data have prompted us to be less hesitant in administration of DLI to PTCy-treated patients when the clinical need arises. Here, we reviewed outcomes of all PTCy-treated patients receiving therapeutic DLI on all HCT protocols in the Center for Immuno-Oncology at the National Cancer Institute from 2015 to 2022.

Materials and methods

Patients

All patients treated across all PTCy-based HCTs not containing prophylactic DLI within the Experimental Transplantation and Immunotherapy Branch/Center for Immuno-Oncology at the National Cancer Institute between December 1, 2015 and September 30, 2022 were included in this study. Decisions on dosing and preparative therapy for therapeutic DLI were at the discretion of the treating physician. The database was locked on March 21, 2023.

Transplant regimens

Conditioning intensity was defined as per consensus criteria [25]. Reduced-intensity conditioning was with (1) pentostatin, low-dose hyper fractionated cyclophosphamide, and two days of busulfan [26] with or without two days of equine anti-thymocyte globulin (ATG) given on days −14 and −13, (2) fludarabine, cyclophosphamide, and 400 cGy total body irradiation, or (3) alemtuzumab (days −14 to −12), fludarabine, and melphalan. Non-myeloablative conditioning was achieved with (1) pentostatin and cyclophosphamide or (2) alemtuzumab (days −21 to −17), cyclophosphamide, and fludarabine. Myeloablative conditioning was with four days of busulfan and fludarabine [27].

Alemtuzumab has a half-life of 12–21 days [28, 29] and thus given between days −14 and −12 is expected to provide significant in vivo T-cell depletion of donor cells. By contrast, equine ATG has a half-life of 5.7 days [30] and was specifically given on days −14 and −13 in an attempt to decrease the extent of in vivo T-cell depletion of donor T cells [31] (i.e., provide primarily host in vivo T-cell depletion).

Outcomes definitions

Indications for DLI were categorized into the following: delayed engraftment, mixed chimerism, poor immune reconstitution/infection, and relapse/progression of malignant disease.

Primary graft failure was defined as failure to achieve engraftment, which in turn was defined as achieving both neutrophil recovery (absolute neutrophil count ≥500 cells/µl for 3 consecutive days) and donor myeloid chimerism ≥5%. Secondary graft failure was defined as achieving initial engraftment but subsequently having donor myeloid chimerism decline to <5% on subsequent measurements. For those that received DLI for delayed engraftment, which was defined as lack of engraftment by day +28 after transplant, only complete response was evaluated, which was defined as achieving engraftment.

Chimerism by short tandem repeats (STR) was determined on CD3+ and CD33+ bead-selected peripheral blood mononuclear cells as per the NIH Clinical Center Department of Laboratory Medicine. Mixed chimerism was defined as myeloid chimerism ≥5% and <95% or donor CD3 chimerism <95%. Patients were reported as having incomplete response after DLI if chimerism remained stable (did not decrease ≥10%) or if it rose to <95%, while complete response was defined as chimerism increasing to ≥95% in both CD3 and myeloid compartments. No response was considered to have occurred if there was >10% decrease in either CD3 or myeloid chimerism or if second HCT was required.

For DLIs administered due to poor immune reconstitution/infection, complete response was considered to have been achieved if at any point after the DLI, there was complete resolution of the infection or virally-associated neoplasm following DLI. Incomplete response was determined if there was objective regression or stability of virally-associated neoplasm but incomplete response was not assessed for other types of infection.

For DLIs given for relapse or progression of the disease, complete response was considered to have been achieved if complete remission was achieved. Disease control without complete remission (i.e., partial response or stable disease) was considered an incomplete response. Response to DLI was considered inevaluable if, in the absence of response, subsequent cellular infusion or death occurred within 27 days.

One patient received 5 DLIs in the setting of uncontrolled human papillomavirus (HPV)-associated recurrent invasive and in situ squamous cell carcinoma (SCC) of the hands and feet as well as anogenital condylomas but he also had mixed chimerism, and thus he was evaluated separately for response for each of these two indications for all five of these DLIs.

CRS grading was by ASTCT consensus criteria [32], acute GVHD grading was by Keystone Criteria [33], and chronic GVHD diagnosis and grading was by NIH Consensus Criteria [34].

Results

Transplant characteristics

A total of 162 patients received 174 PTCy-based HCTs during this time period. Of these patients, 21 received at least one DLI after 22 PTCy-based transplants and were included in this analysis (Table 1). The median patient age was 27 years (range 4–67). Indication for HCT was either to cure malignancy (n = 9), primary immunodeficiency (n = 8), or both (n = 5). Fourteen transplants used an HLA-haploidentical donor, five an HLA-matched-unrelated donor, one an HLA-mismatched-unrelated donor, and two an HLA-matched-sibling donor. Eleven transplants (50%) evaluated in this study used serotherapy (alemtuzumab [n = 3] or equine ATG [n = 8]) as a component of the transplant conditioning regimen.

Table 1.

Recipient, transplantation, and donor lymphocyte infusion (DLI) characteristics.

Total HCTs with DLI (n = 22) Haplo donor (n = 14) MUD (n = 5) mMUD (n = 1) MSD (n = 2)
Male recipient, n 12 8 2 0 2
Recipient age, median (range), years 27 (4–67) 24.5 (4–67) 11 (6–37) 27 35.5 (27–44)
Donor age, median (range), years 31 (17–66) 40 (17–66) 30 (26–43) 29 31 (26–36)
Female donor/male recipient, n 3 2 0 0 1
Indications for transplant, na
   Malignancy 14 10 1 1 2
         AML 1 1 0 0 0
         B-ALL 1 1 0 0 0
         T-cell lymphoma/leukemia 8 5 1 1 1
         B-cell NHL 3 3 0 0 0
         Histiocytic sarcoma 1 0 0 0 1
   Primary immunodeficiency 13 9 4 0 0
CMV serostatus, donor/recipient, n
         +/+ 5 4 0 0 1
         +/− 6 4 2 0 0
         −/+ 3 2 0 0 1
         −/− 5 2 2 1 0
         +/unknownb 2 1 1 0 0
         −/unknownb 1 1 0 0 0
HCT conditioning regimen intensity, n
         Myeloablative 2 2 0 0 0
         Reduced-intensity 16 10 4 0 2
         Non-myeloablative 4 2 1 1 0
HCT graft source, n
         T-cell-replete bone marrow 11 7 3 0 1
         T-cell-replete peripheral blood stem cells 11 7 2 1 1
HCT GVHD prophylaxis regimen, n
        PTCy 50 mg/kg/day on days +3 and +4, MMF, tacrolimus 3 1 2 0 0
        PTCy 50 mg/kg/day on days +3 and +4, MMF, sirolimus 13 8 3 0 2
        PTCy 50 mg/kg/day on days +3 and +4, sirolimus 1 0 0 1 0
            PTCy 50 mg/kg/day on days +3 and +4, tacrolimus, ruxolitinib 1 1 0 0 0
        PTCy 25 mg/kg/day on days +3 and +4, MMF, sirolimus 3 3 0 0 0
         PTCy 25 mg/kg/day on day +4 only, MMF, sirolimus 1 1 0 0 0
Time to 1st DLI post-HCT in days, n
         31–60 7 6 1 0 0
         61–90 6 5 0 1 0
         91–120 0 0 0 0 0
         >120 9 3 4 0 2
Total number of DLI doses received, n
         1 13 9 1 1 2
         2 5 3 2 0 0
         3 2 2 0 0 0
         4 1 0 1 0 0
         5 1 0 1 0 0
Characteristics (All DLIs) Total DLIs (n = 38) Haplo donor (n = 21) MUD (n = 14) mMUD (n = 1) MSD (n = 2)
Indication for DLI, nc
         Mixed donor chimerism 25 13 12 0 0
         Delayed primary engraftmentd 2 2 0 0 0
         Relapse or progression of hematologic malignancy 9 4 2 1 2
         Infection/poor immune reconstitution 7 2 5 0 0
Conditioning pre-DLI, n
         None 28 15 11 1 1
         Steroids only 5 3 2 0 0
         Chemotherapy only 1 0 1 0 0
         Chemotherapy + steroids 4 3 0 0 1
DLI cryopreserved or fresh, n
         Cryopreserved 29 14 13 1 1
         Fresh 9 7 1 0 1
T-cell DLI doses (CD3+ cells/kg), n
         1 × 105 3 3 0 0 0
         5–6 × 105 12 9 3 0 0
         1 × 106 10 3 6 1 0
         2 × 106 4 3 1 0 0
         5 × 106 3 2 1 0 0
         1 × 107 6 1 3 0 2
Toxicity of DLI, n
         Acute GVHD, any grade 3 2 1 0 0
         Chronic GVHD 1 1 0 0 0
         Cytokine release syndrome 3 3 0 0 0
Response to DLI, n
         Graft failure in spite of DLI(s) (n = 14 HCTs) 6 5 1 0 0
         Attainment of full donor myeloid chimerism post-DLI (n = 19)e 1 1 0 0 0
          Attainment of full donor T-cell chimerism post-DLI (n = 24) 3 3 0 0 0
         Stability of chimerism (n = 27) 15 5 10 0 0
         Complete remission of malignancy (n = 9) 1 0 0 1 0
         Mixed response/partial malignancy control (n = 9) 3 2 0 0 1
         Control of infection (n = 7) 7 2 5 0 0
         No significant clinical effect 13 8 4 0 1
Open in a new tab

HCT hematopoietic cell transplantation, Haplo HLA-haploidentical, MUD 10/10 HLA-matched-unrelated donor, mMUD 7/8 HLA-matched-unrelated donor, MSD HLA-matched sibling donor, AML acute myeloid leukemia, B-ALL B-cell acute lymphoblastic leukemia, NHL non-Hodgkin leukemia, CMV cytomegalovirus, GVHD graft-versus-host disease, PTCy post-transplantation cyclophosphamide, MMF mycophenolate mofetil, DLI donor lymphocyte infusion.

aOne patient with PTEN deficiency had both peripheral T-cell lymphoma and B-cell NHL, and 4 other patients were transplanted to treat malignancy in the setting of underlying primary immunodeficiency.

bThree patients who had been on chronic IVIG therapy prior to evaluation for transplant.

cOne patient received 5 DLIs for both mixed chimerism and infection.

dPatients who had partial donor chimerism but failed to have ANC recovery ≥ 500

eOne patient with full donor myeloid chimerism post-DLI had insufficient lymphocyte count for measurement of donor T-cell chimerism prior to death (transplant-related mortality).

DLI characteristics

Thirty-eight DLIs were administered following these 22 HCTs (Table 2). The median time to DLI from HCT was 153 days (range 31–2411 days). Nine of the 22 HCTs were followed by more than one DLI. The primary indication for each DLI was as follows: mixed chimerism (n = 20), relapse or progression of hematologic malignancy (n = 9), poor immune reconstitution or uncontrolled infection (n = 7), and delayed primary engraftment (n = 2), although, as above, one patient received 5 DLIs for the secondary indication of mixed chimerism.

Table 2.

Characteristics and Outcomes of Each Donor Lymphocyte Infusion.

Patient ID Disease type DLI # Donor type Dose Cryo/Fresh Pre-DLI lymphodepletion Pre-HCT serotherapy Achieved full chimerism Time to response (days) Acute GVHD Chronic GVHD CRS Graft failure despite DLI
MIXED CHIMERISM Myeloid T-cell
1 IEI (ADA2 deficiency) 1 MUD 5 × 106/kg cryo Steroids YES (ATG) N N - N N N YES
2a IEI (Idiopathic CD4+ lymphopenia) 1 MUD 5 × 105/kg cryo N N N/A N - N N N N
2 MUD 1 × 106/kg cryo N N N/A N - N N N N
3 MUD 1 × 106/kg cryo N N N/A N - N N N N
4 MUD 1 × 106/kg cryo N N N N - N N N N
5 MUD 1 × 106/kg cryo N N N NE - N N N N
3 IEI (IRF8 mutation) 1 MUD 2 × 106/kg fresh N N N N - N N N N
2 MUD 1 × 107/kg cryo N N N N - N N N N
4 IEI (IFNGR1 deficiency) 1 MUD 5 × 105/kg cryo N N N N - N N N N
2 MUD 5 × 105/kg cryo N N N N - N N N N
3 MUD 1 × 106/kg cryo N N N N - N N N N
4 MUD 1 × 106/kg cryo N N N N - N N N N
5.1 IEI (Activated PI3K delta syndrome)/EBV+ DLBCL 1 haplo 1 × 105/kg fresh N N N N - N N N N
2 haplo 5 × 105/kg cryo N N N N - N N N N
3 haplo 5 × 105/kg cryo N N N N - N N N YES
5.2 IEI (Activated PI3K delta syndrome)/EBV- DLBCL 1 haplo 5 × 105/kg cryo N YES (ALE) N/A YES 13 N N YES N
6 IEI (PTEN deficiency)/Peripheral T-cell lymphoma and EBV+ lymphomatoid granulomatosis 1 haplo 5 × 105/kg fresh N N N N - N N N N
2 haplo 2 × 106/kg cryo N N N N - N N N YES
7 IEI (Activated PI3K delta syndrome) 1 haplo 5 × 106/kg cryo N YES (ALE) N/A YES 14 YES N YES N
8 IEI (NFKB1 haploinsufficiency) 1 haplo 1 × 106/kg fresh N N N N - N N N N
2 haplo 5 × 106/kg cryo N N N N - N N N YES
9 B-cell acute lymphoblastic leukemia 1 haplo 1 × 105/kg fresh Steroids N N/A N - N N N N
10 Acute myeloid leukemia 1 haplo 5 × 105/kg fresh Steroids N N/A N - N N N N
2 haplo 2 × 106/kg cryo N N N N - N N N YES
11 IEI (unspecified)/Chronic active EBV, T-cell type 1 haplo 5 × 105/kg cryo Steroids YES (ATG) N/A YES 105 YES N N N
DELAYED PRIMARY ENGRAFTMENT
12 IEI (MAGT1 deficiency) 1 haplo 5 × 105/kg fresh N N YES NE 5 N N N N
13 IEI (unspecified)/Anaplastic large cell lymphoma 1 haplo 6 × 105/kg cryo N YES (ATG) NE NE - N N YES YES
RELAPSE
Malignancy Best response Response at last follow-up
14 Anaplastic large cell lymphoma 1 MUD 1 × 107/kg cryo Chemo YES (ATG) PD PD - N N N
2 MUD 1 × 107/kg cryo Steroids YES (ATG) PD PD - YES N N
15 Histiocytic sarcoma 1 MSD 1 × 107/kg fresh N N IR PD - N N N
16 NK/T-cell lymphoma 1 MSD 1 × 107/kg cryo Chemo/Steroids YES (ATG) PD PD - N N N
17 Adult T-cell lymphoma/leukemia 1 haplo 1 × 106/kg cryo Chemo/Steroids YES (ATG) PD PD - N N N
18 Hepatosplenic γδ T-cell lymphoma 1 haplo 1 × 106/kg cryo N YES (ATG) IR IR - N N N
2 haplo 2 × 106/kg cryo Chemo/Steroids YES (ATG) IR IR - N N N
3 haplo 1 × 107/kg cryo Chemo/Steroids YES (ATG) PD PD - N N N
19 Cutaneous T-cell lymphoma 1 mMUD 1 × 106/kg cryo N YES (ALE) CR CR 37 N N N
INFECTION
20 Cytomegalovirus pneumonitis 1 haplo 1 × 105/kg fresh N N CR CR 42 N N N
21 Adenovirus viremia 1 haplo 5 × 105/kg cryo N YES (ATG) CR CR 20 N YES N
2a HPV-associated squamous cell carcinoma 1 MUD 5 × 105/kg cryo N N IR IR - N N N
2 MUD 1 × 106/kg cryo N N IR IR - N N N
3 MUD 1 × 106/kg cryo N N IR IR - N N N
4 MUD 1 × 106/kg cryo N N IR IR - N N N
5 MUD 1 × 106/kg cryo N N IR NR - N N N
Open in a new tab

ALE alemtuzumab, ATG equine anti-thymocyte globulin, Cryo cryopreserved cells, CR complete response, CRS cytokine release syndrome, DLI donor lymphocyte infusion, EBV Epstein-Barr Virus, haplo HLA-haploidentical donor, HPV human papillomavirus, GVHD Graft-versus-host disease, IEI inborn error of immunity, IR incomplete response, MUD 10/10 HLA-matched-unrelated donor, MSD HLA-matched sibling donor, mMUD 7/8 HLA-matched-unrelated donor, N no, N/A not applicable as these patients had full myeloid chimerism at time of DLI, NE not evaluable due to too few white blood cells numbers to run chimerism assay, NR no response, PR progression of disease.

aThis patient is listed twice as DLI was given for both mixed chimerism and infection (virally-driven squamous cell carcinoma of hands, feet, thighs) who had stability of both viral lesions and chimerism after each DLI.

The majority of the DLIs were unconditioned (n = 28), and of the 10 that received conditioning, 5 received corticosteroids alone, 4 received chemotherapy and corticosteroids, and 1 received chemotherapy alone (Table 2 and Table 3). In four patients <120 days post-transplant at the time of DLI, ongoing GVHD prophylaxis with sirolimus (n = 5 DLIs) or tacrolimus (n = 1 DLI) was continued after DLI (Table 3). Most DLI products were cryopreserved (n = 29), while 9 were given from a fresh collection. DLI doses ranged from 1 × 105 to 1 × 107 T cells/kg.

Table 3.

Characteristics of each DLI.

Donor type Dose of DLI Cryopreserved or fresh G-CSF-primed* Immunosuppression after DLI Conditioning
Toxicity of DLI, n (%) Total DLIs (n = 38) Haplo (n = 21) MUD (n = 14) mMUD (n = 1) MSD (n = 2) 1 × 105 (n = 3) 5–6 × 105 (n = 12) 1 × 106 (n = 10) 2 × 106 (n = 4) 5 × 106 (n = 3) 1 × 107 (n = 6) Cryo (n = 29) Fresh (n = 9) Yes (n = 13) No (n = 25) Yes (n = 6) No (n = 32) Chemotherapyc (n = 5) Steroids only (n = 5) None (n = 28)
  Acute GVHD, any grade 3 2 1 0 0 0 1 0 0 1 1 3 0 2 1 0 3 0 2 1
  Chronic GVHD 1 1 0 0 0 0 1 0 0 0 0 1 0 1 0 1 0 0 0 1
  Cytokine release syndrome 3 3 0 0 0 0 2 0 0 1 0 3 0 3 0 0 3 0 0 3
Response To DLIa
  Attainment of full donor myeloid chimerism post-DLI (n = 19) 1 1 0 0 0 0 1 0 0 0 0 0 1 0 1 0 1 0 0 1
  Attainment of full donor T-cell chimerism post-DLI (n = 24) 3 3 0 0 0 0 2 0 0 1 0 3 0 3 0 0 3 0 1 2
  Stability of chimerism (n = 27)b 15 5 10 0 0 2 6 6 1 0 0 11 4 0 15 1 14 0 1 14
  Complete remission of malignancy (n = 9) 1 0 0 1 0 0 0 1 0 0 0 1 0 1 0 0 1 0 0 1
  Mixed response/partial malignancy control (n = 9) 3 2 0 0 1 0 0 1 1 0 1 2 1 2 1 0 3 1 0 2
  Control of infection (n = 7) 7 2 5 0 0 1 2 4 0 0 0 6 1 1 6 1 6 0 0 7
  No significant clinical effect (NR or PD) 13 8 4 0 1 0 2 2 2 2 5 11 2 6 7 4 9 3 3 7
Open in a new tab

DLI donor lymphocyte infusion, Haplo HLA-haploidentical donor, MUD 10/10 HLA-matched-unrelated donor, mMUD 7/8 HLA-matched-unrelated donor, MSD HLA-matched sibling donor, Cryo cryopreserved, NR no response, PD progression of disease.

*excess cells from a PBSC graft were aliquoted and cryopreserved for future DLI use.

a1 patient received 5 MUD DLIs for infection and mixed chimerism and thus these DLIs are counted in each category.

b1 patient had stable myeloid chimerism but had too few cells to evaluate CD3 chimerism after his last DLI.

C Patients who received steroids with chemotherapy were included in this group.

Toxicity

Out of 38 DLIs administered, we observed only 3 cases of acute GVHD (one grade II and two grade III), 3 cases of cytokine release syndrome (CRS), and one case of chronic GVHD in a total of 6 patients (Fig. 1, Table 2). All six of the patients with toxicity received serotherapy as part of their conditioning (2 received alemtuzumab and 4 received equine ATG) (Fig. 1, Table 2).

Fig. 1. Toxicity of DLI.

Fig. 1

Open in a new tab

a–c Toxicity of DLI based on occurrence of a cytokine release syndrome (CRS), b acute GVHD (aGVHD), or c either CRS or acute or chronic GVHD after each individual DLI. d–f Toxicity is also illustrated per hematopoietic cell transplant (HCT) based on occurrence of d CRS, e acute GVHD or f any CRS or acute or chronic GVHD, showing that CRS or GVHD occurred only in those that received serotherapy prior to HCT.

Two different patients had other immune phenomena occur later post-DLI: juvenile dermatomyositis with systemic lupus erythematosus 1 year after the most recent DLI and vitiligo 149 days following the first DLI.

Efficacy

The success of each DLI was assessed based on the indication. For six out of the 12 HCTs (50%) in which DLI was given for mixed chimerism, there was no sustained response [35], with 5 of these patients experiencing secondary graft failure despite DLI (Figs. 2 and 3, Table 2); three patients had incomplete responses with two patients continuing to have stable mixed chimerism for >1 year and another having uptrending but low (33%) donor T-cell chimerism 6 months later at the time of death from relapsed leukemia. Of the 6 patients treated for relapsed/progressive hematologic malignancy, one patient had complete response, 2 patients had partial response (duration of response 57 and 102 days), and 3 had no response. Among the two patients given DLI for delayed primary engraftment (mixed chimerism and absolute neutrophil count <500 cells/µl), one promptly engrafted 5 days after DLI administration (day +40) [36], while the other had loss of transient mixed chimerism and confirmed primary graft failure.

Fig. 2. Response to DLI.

Fig. 2

Open in a new tab

a–c Response to DLI with respect to indication for DLI is shown as (a, b) best response by a DLI or b transplant, and c response at last follow-up for each patient. d Complete responses were most often seen in DLIs given after HCT conditioned with serotherapy, but response was not seemingly affected based on e whether the DLI had been cryopreserved (cryo) vs. fresh or f whether a low-dose or standard-dose DLI was given. Standard doses of DLI were considered to be ≥1 × 106 for HLA-partially-mismatched donors or 1 × 107 for HLA-matched donors. g Best response is shown per patient based on indication for DLI and whether serotherapy had been used as conditioning for the HCT after which DLI was given. CR complete response, IR incomplete response, NR no response, PD progressive disease.

Fig. 3. Responses to DLI of Patients with Mixed Chimerism Only in Those Who Had Received Pre-Transplant Serotherapy.

Fig. 3

Open in a new tab

DLI was given for mixed chimerism after 12 HCTs, of which a only three resulted in complete donor chimerism. All three of these patients had received pre-HCT serotherapy. b Of 9 patients who did not achieve complete donor chimerism after DLI, only one (patient 1) received serotherapy prior to transplant. 4 patients achieved stable chimerism (patients 2, 3, 4, and 9; the response of patient 3 was stable only after the first DLI with progressive chimerism decline after the second DLI) and 5 patients had secondary graft failure (patients 1, 5 with 1st HCT, 6, 8, and 10), although patient 6 did have stability of chimerism after his first DLI and patient 5 did have stability of chimerism after her first two DLIs before both patients exhibited secondary graft failure following their final DLIs. Patient numbers shown correspond to the numbering used in Table 2.

By contrast, all patients who received DLI for infection resultant from poor immune reconstitution had response: 1 incomplete and 2 complete. Our previously mentioned patient (Patient #2 in Table 2) with incomplete response was a subject with idiopathic CD4 lymphopenia [37] who had HPV-associated SCC existing prior to HCT and post-HCT had both mixed chimerism and poor immune reconstitution. He received a total of 5 DLIs, and, with each DLI and concurrent surgical debridement, we noticed partial regression of the SCC on his hands and feet (Fig. 4) in the absence of any notable toxicity. However, before a more definitive solution (second HCT or systemic therapy for SCC) could be attained, he was incarcerated and his SCC progressed with time. A second patient (Patient #20 in Table 2), who was CMV-naïve pre-HCT, developed CMV pneumonitis requiring prolonged extra-corporeal membrane oxygenation and need for continuous renal replacement therapy 7 months post-HCT after primary CMV infection. Given her dire clinical situation, on day +236, she received DLI from her CMV-seronegative donor to help control her CMV infection, and she recovered completely from the infection. A third patient (Patient #21 in Table 2) had high-level adenoviremia at 1 month post-HCT which was fully controlled after DLI administration and concurrent de-escalation of GVHD prophylaxis.

Fig. 4. Transient regressions of HPV-associated squamous cell carcinoma (SCC) of the hands and feet in patient 2.

Fig. 4

Open in a new tab

A patient with idiopathic CD4 lymphopenia had HPV-associated SCC lesions affecting the hands and feet. a–c Evolution of these lesions are shown in relation to DLI administration. Overall, there were transient regressions seen in these lesions as shown after b DLI #3 and c DLI #4 with adjunctive surgical debridement as compared to (a) SCC lesions shown before any DLI administration, along with subjective improvements noted by the patient such as slower growth and decreased pain.

In evaluating cofactors that may correlate with response to DLI, pre-transplant serotherapy seemed to correlate both with response and associated toxicity (Figs. 1 and 2), with a larger number of complete responses noted after DLI after transplants with conditioning serotherapy (35% vs 8.3% of DLIs led to complete response) and all CRS and GVHD events occurring after DLI in patients receiving pre-transplant serotherapy as above (43% vs. 0% of DLIs led to GVHD or CRS).

Discussion

We have found that patients receiving PTCy-based HCT and therapeutic DLI had overall low rates of GVHD or CRS with only three cases of acute GVHD (14% of patients, 8% of DLIs), three cases of CRS (14% of patients, 8% of DLIs), and one case of late-onset chronic GVHD among six patients. All patients who had acute GVHD, CRS, or chronic GVHD had received serotherapy prior to HCT as part of their conditioning regimen. The rates of complete response to DLI by indication were low at 11% for relapse and 15% for mixed chimerism or delayed engraftment, but we did see some apparent efficacy, albeit with small numbers, when using DLI for infection with two of three patients having complete response (incomplete response only in treatment of HPV-associated SCC). Of patients receiving serotherapy-containing pre-HCT conditioning, there appeared to be more complete responses overall, which was particularly apparent for the treatment of mixed chimerism, than when compared with patients not receiving serotherapy.

Although our numbers of patients are limited, the rates of acute GVHD from DLI appear low compared with other studies employing therapeutic HLA-matched or HLA-partially-mismatched DLIs without PTCy (35–60% acute GVHD) [3, 4, 7, 8, 9, 12]. This result is consistent with our preclinical data showing that PTCy induces Treg-mediated suppressive mechanisms that minimize GVHD induction by subsequent cell infusions [15, 16, 20]. The rates of GVHD after DLI in our patients are even lower than those reported in some other studies of PTCy-treated patients [22–24]. It is possible that this is attributable to the lack of pre-DLI conditioning in many of our patients, as lymphodepleting chemotherapy prior to DLI is associated with higher rates of GVHD [11, 12, 14, 38, 39]; even so, in our limited dataset, we did not see any seeming correlation between pre-DLI conditioning and toxicity or efficacy. Other factors could contribute such as the use of sirolimus (conducive to Treg recovery) rather than tacrolimus for 73% of our patients or the use of lower-dose DLI in many cases. Many DLIs were administered for mixed chimerism or infection wherein a clinical benefit was intended but there was a strong interest in minimizing risk for GVHD; therefore, a low starting dose was often used for the first DLI with subsequent doses being escalated. Even so, the dosing of DLI did not seem to correlate strongly with toxicity or response (Table 2 and Fig. 2f). Lastly, many cryopreserved and/or granulocyte-colony stimulating factor-primed (aliquoted from original cryopreserved PBSC graft) DLIs were used; although it is possible that this may have contributed to our overall low rates of response and toxicity [40], all toxicity events actually occurred in patients receiving cryopreserved DLI so this possibility is unlikely.

Consistent with the attenuation of alloreactivity, the therapeutic efficacy of these DLIs also was limited, except for control of infection (a non-alloreactive response). DLI is heterogeneously effective across diseases, with very high response rates in CML, but much lower response rates in AML and very poor responses in ALL or B-cell lymphomas. Most of our patients treated for relapse with DLI had T-cell diseases (adult T-cell leukemia/lymphoma, anaplastic large cell lymphoma, hepatosplenic T-cell lymphoma, NK/T-cell lymphoma); DLI has a relatively high response rate of 44–66% in adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma [41, 42], but uncertainty of response for many other T-cell diseases. The seemingly low rate of response in our cohort may be due to the heterogeneity of diseases treated with DLI and the variable susceptibility of these diseases to immune-mediated therapy. Additionally, we were unable to evaluate for loss of HLA-haplotype as a potential mechanism of immune evasion in all patients who received an HLA-haploidentical DLI (one non-responding patient was confirmed not to have had HLA loss), and this could have contributed to the low response rate. Lastly, the lack of lymphodepleting conditioning immediately prior to DLI for most of our DLIs again may have contributed to the low response rate seen [9, 11–14].

Yet, the attenuated response to DLI seen appears partially modifiable by pre-HCT serotherapy as all six patients with GVHD or CRS had had serotherapy (ATG or alemtuzumab) as part of pre-HCT conditioning. A prospective trial investigating prophylactic DLI given to patients with AML or ALL receiving alemtuzumab as pre-transplant conditioning also noted a high rate of GVHD (7 out of 16 patients) with 3 patients dying from steroid-refractory grade III acute GVHD despite low-dose DLI in two of these patients (<1 × 106 T cells/kg) [43]. These results lead us to postulate that pre-transplant serotherapy may potentially disrupt the suppressive mechanisms, particularly expansion of Tregs, induced by PTCy, interfering with their protection against GVHD inducible by subsequent T-cell infusions [15, 20]. In fact, when Tregs are higher post-DLI as in the case of NK-cell-enriched infusions, there was markedly less GVHD than the same platforms without DLI in which levels of Tregs were lower [44].

The apparent therapeutic response to DLI when used for infectious indications was encouraging. However, it is impossible to definitively attribute enhanced immune reconstitution/therapeutic effect to the DLI only and not just to resolution with time or control of the infection by donor immune cells previously received during the transplant. Moreover, it has been previously demonstrated that DLI has effects on donor immune cells already present in the recipient [45], so the distinction becomes even more challenging. Lastly, some patients were receiving concurrent anti-viral therapy or had decreases in immunosuppression, which may have contributed.

There are several limitations to our retrospective study. Although our study has comparable patient numbers as other reports of DLI for PTCy-treated patients [22–24], our study is still modest in size. Moreover, there is a heterogeneous patient population with diverse indications for DLI and the primary HCT platforms varied including different donor types. Additionally, DLI sources were not uniform as some were aliquoted from mobilized PBSC grafts while others were harvested from separate peripheral blood collections without filgrastim exposure. DLI doses ranged from 105 to 107 T cells/kg and the time to DLI from HCT varied greatly as well from day +31 to day +2411. This variability in disease type; HCT platform; DLI dose, source, and timing; and HLA-matching limits our ability to draw more definitive generalized conclusions from our data. Moreover, our institution is a research hospital, with all patients transplanted on a research study, each of which utilize proscribed transplant platforms for particular patient populations. Serotherapy was a component of the transplant platform for only two of the five studies included in this study, and thus there is the possibility of selection bias particularly related to disease types and treatment history among patients that received serotherapy (these two studies were for patients with T-cell lymphoma [NCT03922724] or immune dysregulation/inborn errors of immunity (IEI) [NCT03663933], whereas two of the three studies not using serotherapy were for all hematologic malignancies (NCT03983850 and NCT04959175, both of which largely enrolled acute leukemias) and the third (NCT02579967) was for IEI). Nevertheless, the transplant platform is nearly identical between the two serotherapy studies and the serotherapy-free IEI study; only three of the 22 HCTs occurred on the other two protocols that enrolled all types of hematologic malignancies. While we considered applying formal statistical analysis to assess the effects of serotherapy or other factors on outcomes, the substantial interpatient and DLI characteristic heterogeneity made such formal statistical comparisons in this small sample size not meaningful, and thus we opted to provide only descriptive statistics.

Despite the wide variety of therapeutic indications, diseases, and DLI conditions of our cohort, it does appear that DLI administered after PTCy has low rates of GVHD, but strategies to improve DLI efficacy are needed. Given encouraging results with prophylactic DLIs, it is possible that administering DLIs earlier might promote activity before the suppressive mechanisms are fully established [46, 47]. Our preclinical data, however, suggest that this window may be brief in PTCy-treated recipients [48]. Since our DLIs for relapse were all administered beyond post-HCT day +31, we may have missed a window of efficacy for the DLI. We are testing this potential for very early prophylactic DLI to effect a better anti-tumor response for high-risk malignancies in an ongoing clinical trial (NCT05327023). Alternative approaches include NK-cell-based therapies, which have the advantage of minimal risk of GVHD [49, 50]. Nevertheless, we have demonstrated that T-cell-containing DLI with PTCy also are safe with low rates of alloreactivity, and thus we may not need to limit our therapeutic options for post-HCT relapse to NK-cell therapies alone.

Even so, the safety of DLIs given to our patients is a double-edged sword. The therapeutic intent of DLI, except for infection, is to induce a better graft-versus-host response against residual malignancy or normal host hematopoiesis. Yet, DLI, while safe, may have low efficacy in treating relapse or stabilizing graft function unless given in the setting of serotherapy-containing pre-HCT conditioning. Thus, novel therapies are needed in PTCy-treated patients to exert a stronger anti-tumor or anti-host hematopoiesis response and overcome the immunosuppressive environment induced by PTCy but still not incite GVHD.

Author contributions

JAK and CGK designed the study. KS and SN contributed to the study design. KS and SN collected data. KS, SN, DD, JAK, and CGK analyzed and interpreted data. AS, JW, AC, AL, MVA, IS, GU, AFF, CM, JS, RS, KR, and MAH contributed to data interpretation as well as care of patients treated with DLI on this study. KS, SN, DD, JAK, and CGK also provided care of patients treated with DLI on this study. KS, SN, JAK, and CGK prepared figures and tables. KS and CGK wrote the manuscript, and all authors revised the manuscript.

Funding

This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and by the Lasker Foundation. Open access funding provided by the National Institutes of Health.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

After informed consent, all patients were transplanted on one of several National Institutes of Health Institutional Review Board-approved studies (NCT02579967, NCT03663933, NCT03922724, NCT03983850, or NCT04959175). Consent was obtained for clinical photography. This research was performed in accordance with the Declaration of Helsinki.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Scott Napier, Dimana Dimitrova.

These authors jointly supervised this work: Jennifer A. Kanakry, Christopher G. Kanakry.

Contributor Information

Jennifer A. Kanakry, Email: jennifer.kanakry@nih.gov

Christopher G. Kanakry, Email: christopher.kanakry@nih.gov

References

  • 1.Auletta JJ, Kou J, Chen M, Bolon Y-T, Broglie L, Bupp C, et al. Real-world data showing trends and outcomes by race and ethnicity in allogeneic hematopoietic cell transplantation: a report from the Center for International Blood and Marrow Transplant Research. Transplant Cell Ther. 2023;29:346.e1–348.e10. [DOI] [PMC free article] [PubMed]
  • 2.Chalandon Y, Passweg JR, Guglielmi C, Iacobelli S, Apperley J, Schaap NP, et al. Early administration of donor lymphocyte infusions upon molecular relapse after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia: a study by the Chronic Malignancies Working Party of the EBMT. Haematologica. 2014;99:1492–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Collins R Jr, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R, et al. Donor leukoocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15:433–44. [DOI] [PubMed] [Google Scholar]
  • 4.Kolb HJ, Goldman JM, Bernd H, Jacobsen N, Arcese W, Ljungman P, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86:2041–50. [PubMed] [Google Scholar]
  • 5.Ho VT, Alyea EP. Donor lymphocyte infusions. Adv Pharmacol. 512004. [DOI] [PubMed]
  • 6.Roush KS, Hillyer CD. Donor lymphocyte infusion therapy. Transfus Med Rev. 2002;16:161–76. [DOI] [PubMed] [Google Scholar]
  • 7.Or R, Hadar E, Bitan M, Resnick IB, Aker M, Ackerstein A, et al. Safety and efficacy of donor lymphocyte infusions following mismatched stem cell transplantation. Biol Blood Marrow Transpl. 2006;12:1295–301. [DOI] [PubMed] [Google Scholar]
  • 8.Schmid C, Labopin M, Nagler A, Bornhauser M, Finke J, Fassas A, et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol. 2007;25:4938–45. [DOI] [PubMed] [Google Scholar]
  • 9.Collins Jr R, Goldstein S, Johnson M, Kirk A, Giralt S, Horowitz M, et al. Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant. 2000;26:511–6. [DOI] [PubMed] [Google Scholar]
  • 10.Haines HL, Bleesing JJ, Davies SM, Hornung L, Jordan MB, Marsh RA, et al. Outcomes of donor lymphocyte infusion for treatment of mixed donor chimerism after a reduced-intensity preparative regimen for pediatric patients with nonmalignant diseases. Biol Blood Marrow Transplant. 2015;21:288–92. [DOI] [PubMed]
  • 11.Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol. 2002;20:405–12. [DOI] [PubMed] [Google Scholar]
  • 12.Huff CA, Fuchs EJ, Smith BD, Blackford A, Garrett-Mayer E, Brodsky RA, et al. Graft-versus-host reactions and the effectiveness of donor lymphocyte infusions. Biol Blood Marrow Transpl. 2006;12:414–21. [DOI] [PubMed] [Google Scholar]
  • 13.Salama M, Nevill T, Marcellus D, Parker P, Johnson M, Kirk A, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. 2000;26:1179–84. [DOI] [PubMed]
  • 14.Warlick ED, DeFor T, Blazar BR, Burns L, Verneris MR, Ustun C, et al. Successful remission rates and survival after lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies postallogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2012;18:480–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Gress RE, Kanakry CG. Posttransplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Investig. 2019;129:2357–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Kanakry CG, Ganguly S, Zahurak M, Bolaños-Meade J, Thoburn C, Perkins B, et al. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med. 2013;5:211ra157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Nunes NS, Kanakry CG. Mechanisms of graft-versus-host disease prevention by post-transplantation cyclophosphamide: an evolving understanding. Front Immunol. 2019;10:2668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Ganguly S, Ross DB, Panoskaltsis-Mortari A, Kanakry CG, Blazar BR, Levy RB, et al. Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood. 2014;124:2131–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Kanakry CG, Fuchs EJ, Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol. 2016;13:10–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Fletcher RE, Nunes NS, Patterson MT, Vinod N, Khan SM, Mendu SK, et al. Posttransplantation cyclophosphamide expands functional myeloid-derived suppressor cells and indirectly influences tregs. Blood Adv. 2023;7:1117–29. [DOI] [PMC free article] [PubMed]
  • 21.Ghiso A, Raiola A, Gualandi F, Dominietto A, Varaldo R, Maria Teresa VL, et al. DLI after haploidentical BMT with post-transplant CY. Bone Marrow Transplant. 2015;5056–61. [DOI] [PubMed]
  • 22.Goldsmith SR, Slade M, DiPersio JF, Westervelt P, Schroeder MA, Gao F, et al. Donor-lymphocyte infusion following haploidentical hematopoietic cell transplantation with peripheral blood stem cell grafts and PTCy. Bone Marrow Transpl. 2017;52:1623–8. [DOI] [PubMed] [Google Scholar]
  • 23.Zeidan AM, Forde PM, Symons H, Chen A, Smith BD, Pratz K, et al. HLA-haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transpl. 2014;20:314–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Jaiswal SR, Zaman S, Chakrabarti A, Sen S, Mukherjee S, Bhargava S, et al. Improved outcome of refractory/relapsed acute myeloid leukemia after post-transplantation cyclophosphamide-based haploidentical transplantation with myeloablative conditioning and early prophylactic granulocyte colony-stimulating factor-mobilized donor lymphocyte infusions. Biol Blood Marrow Transpl. 2016;22:1867–73. [DOI] [PubMed] [Google Scholar]
  • 25.Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl. 2009;15:1628–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Dimitrova D, Gea-Banacloche J, Steinberg SM, Sadler JL, Hicks SN, Carroll E, et al. Prospective study of a novel, radiation-free, reduced-intensity bone marrow transplantation platform for primary immunodeficiency diseases. Biol Blood Marrow Transpl. 2020;26:94–106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Kanakry CG, O’Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M, et al. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014;32:3497–505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Marsh RA, Fukuda T, Emoto C, Neumeier L, Khandelwal P, Chandra S, et al. Pretransplant absolute lymphocyte counts impact the pharmacokinetics of alemtuzumab. Biol Blood Marrow Transplant. 2017;23:635–41. [DOI] [PubMed] [Google Scholar]
  • 29.Frampton JE, Wagstaff AJ. Alemtuzumab. Drugs. 2003;63:1229–43. [DOI] [PubMed] [Google Scholar]
  • 30.Pfizer. Package Insert- ATGAM. New York, NY: Food and Drug Administration; 1981.
  • 31.Rechache K, Dimitrova D, Feng X, Flomerfelt F, Napier S, Sponaugle J, et al. Distally-timed equine antithymocyte globulin (eATG) in allogeneic hematopoietic cell transplantation (HCT) conditioning – pharmacokinetics and the relationship between total E-ATG levels, pre-HCT absolute lymphocyte count, immune reconstitution, and graft-versus-host responses. Transplant Cell Ther. 2022;28:S1–509.
  • 32.Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transpl. 2019;25:625–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transpl. 1995;15:825–8. [PubMed] [Google Scholar]
  • 34.Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transpl. 2015;21:389–401.e1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Manion M, Dimitrova D, Pei L, Gea-Banacloche J, Zelazny A, Lisco A, et al. Immune reconstitution inflammatory syndrome as a posttransplantation complication in primary immunodeficiency with disseminated Mycobacterium avium. Clin Infect Dis. 2020;70:676–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Dimitrova D, Rose JJ, Uzel G, Cohen JI, Rao KV, Bleesing JH, et al. Successful bone marrow transplantation for XMEN: hemorrhagic risk uncovered. J Clin Immunol. 2019;39:1–3. [DOI] [PubMed] [Google Scholar]
  • 37.Lisco A, Ortega-Villa AM, Mystakelis H, Anderson MV, Mateja A, Laidlaw E, et al. Reappraisal of idiopathic CD4 lymphocytopenia at 30 years. N. Engl J Med. 2023;388:1680–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Guillaume T, Gaugler B, Chevallier P, Delaunay J, Ayari S, Clavert A, et al. Escalated lymphodepletion followed by donor lymphocyte infusion can induce a graft-versus-host response without overwhelming toxicity. Bone Marrow Transplant. 2012;47:1112–7. [DOI] [PubMed] [Google Scholar]
  • 39.Miller JS, Weisdorf DJ, Burns LJ, Slungaard A, Wagner JE, Verneris MR, et al. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood. 2007;110:2761–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Maurer K, Kim HT, Garrity HM, Liney D, Cutler C, Antin JH, et al. Lower incidence of chronic GVHD observed after transplantation with cryopreserved unrelated allogeneic stem cells. Blood Adv. 2023;7:2431–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Itonaga H, Tsushima H, Taguchi J, Fukushima T, Taniguchi H, Sato S, et al. Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: the Nagasaki Transplant Group experience. Blood. 2013;121:219–25. [DOI] [PubMed] [Google Scholar]
  • 42.Dodero A, Spina F, Narni F, Patriarca F, Cavattoni I, Benedetti F, et al. Allogeneic transplantation following a reduced-intensity conditioning regimen in relapsed/refractory peripheral T-cell lymphomas: long-term remissions and response to donor lymphocyte infusions support the role of a graft-versus-lymphoma effect. Leukemia. 2012;26:520–6. [DOI] [PubMed] [Google Scholar]
  • 43.Liga M, Triantafyllou E, Tiniakou M, Lambropoulou P, Karakantza M, Zoumbos NC, et al. High alloreactivity of low-dose prophylactic donor lymphocyte infusion in patients with acute leukemia undergoing allogeneic hematopoietic cell transplantation with an alemtuzumab-containing conditioning regimen. Biol Blood Marrow Transpl. 2013;19:75–81. [DOI] [PubMed] [Google Scholar]
  • 44.Jaiswal SR, Zaman S, Nedunchezhian M, Chakrabarti A, Bhakuni P, Ahmed M, et al. CD56-enriched donor cell infusion after post-transplantation cyclophosphamide for haploidentical transplantation of advanced myeloid malignancies is associated with prompt reconstitution of mature natural killer cells and regulatory T cells with reduced incidence of acute graft versus host disease: a pilot study. Cytotherapy. 2017;19:531–42. [DOI] [PubMed] [Google Scholar]
  • 45.Bachireddy P, Hainz U, Rooney M, Pozdnyakova O, Aldridge J, Zhang W, et al. Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion. Blood. 2014;123:1412–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Rettig AR, Ihorst G, Bertz H, Lübbert M, Marks R, Waterhouse M, et al. Donor lymphocyte infusions after first allogeneic hematopoietic stem-cell transplantation in adults with acute myeloid leukemia: a single-center landmark analysis. Ann Hematol. 2021;100:2339–50. [DOI] [PMC free article] [PubMed]
  • 47.Harada K, Mizuno S, Yano S, Takami A, Ishii H, Ikegame K, et al. Donor lymphocyte infusion after haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia. Ann Hematol. 2022;101:643–53. [DOI] [PubMed] [Google Scholar]
  • 48.Patterson MT, Khan SM, Nunes NS, Fletcher RE, Bian J, Hadjis AD, et al. Murine allogeneic CAR-T cells integrated before or early after posttransplant cyclophosphamide exert anti-tumor effects. Blood. 2023;141:659–72. [DOI] [PMC free article] [PubMed]
  • 49.Passweg JR, Tichelli A, Meyer-Monard S, Heim D, Stern M, Kühne T, et al. Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia. 2004;18:1835–8. [DOI] [PubMed] [Google Scholar]
  • 50.Vacca P, Pietra G, Tumino N, Munari E, Mingari MC, Moretta L. Exploiting human NK cells in tumor therapy. Front Immunol. 2019;10:3013. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Articles from Bone Marrow Transplantation are provided here courtesy of Nature Publishing Group

RESOURCES