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Dose escalation prophylactic donor lymphocyte infusion after T-cell depleted matched related donor allogeneic hematopoietic cell transplantation is feasible and results in higher donor chimerism, faster immune re-constitution, and prolonged progression-free survival


Prophylactic donor lymphocyte infusion (pDLI) is a potential intervention to prolong remission for patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT), however, the optimal timing and dose are unknown. We conducted a prospective trial exploring the feasibility of early withdrawal of immunosuppression (WOI) at day 60 followed by dose escalation of pDLI after alemtuzumab-based, T-cell depleted conditioning for patients with high-risk hematologic malignancies. pDLI were administered at day 75 to day 90 and again in 4–8 week intervals with receipt of up to 5 pDLI infusions. Fourty-six patients with matched-related donors (MRD) and 29 patients with matched-unrelated donors (MUD) were considered. Twenty-eight MRD patients were able to undergo WOI, 26 patients (93%) received at least 1 DLI, 16 patients (57%) received 3+, and 7 patients (25%) received 5 pDLI. Only 7 MUD patients were able to undergo WOI, 4 (57%) received at least 1 pDLI, 1 patient (14%) received 3 DLI, and no patients received all 5. Median PFS for patients on the study was 366 days. The estimated 2-year PFS and OS rates for all patients were 41% (95% CI, 32–54%) and 51% (95% CI, 41–63%) compared with 57% (95% CI, 41–77%) and 67% (95% CI, 52–86%) for patients who received at least one pDLI. In addition, MRD patients receiving pDLI had faster immune re-constitution and improved donor chimerism. Our trial proposes a novel dosage and treatment schedule for pDLI that is tolerable for patients who have received MRD allo-SCT and leads to improved outcomes.


Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potential curative treatment for many patients with hematologic malignancies. Decades of experience have led to improved protocols that limit the risks of graft-versus-host disease (GVHD) and help many patients achieve long-lasting remission. Despite this progress, relapse remains a major complication and few therapeutic options are available to these patients. Our center has attempted second allo-SCT with some benefit, though many patients eventually die from disease progression [1].

One option to prevent relapse has been the deployment of donor lymphocyte infusions (DLI). DLI have been shown to be effective as a “proactive” strategy in several settings in which risk of relapse is increased due to changes in mixed donor chimerism, evidence of persistent minimal residual disease, or molecular relapse [2,3,4,5]. Furthermore, several studies have shown that “prophylactic” DLI (pDLI) can improve survival when given to patients without evidence of recurrent disease [6, 7]. Though the majority of studies reporting on these outcomes have been retrospective, several prospective studies of pDLI have shown positive outcomes [8,9,10,11,12,13].

As the evidence for pDLI use grows, several questions remain about best practices. It is unclear when in the post-transplant course immunosuppression should be withdrawn and the deployment of pDLI should begin. Furthermore, there exists no consensus on the appropriate dose of pDLI that should be used to achieve anti-leukemic effects while avoiding the risk of GVHD. Existing studies have used various start dates and doses. For example, Schmid et al. in 2019 reported on a retrospective registry analysis in which patients received first pDLI anytime between 42 and 346 days post allo-SCT [6]. Similarly, Jedlickova et al. reported on a prospective trial of 46 patients in which the range of time from transplantation to first DLI was 71–303 days [14].

Given the heterogeneity across pDLI studies, there is need for a systematic study that helps identify an effective treatment schedule and dosing strategy. To address this gap, we performed a prospective trial evaluating the feasibility and outcomes of a specified treatment schedule for pDLI in patients undergoing allo-SCT.

Materials and methods

Study design and treatment

This was an open-label study assessing administration of pDLI in patients with high-risk hematologic malignancies who had received allo-SCT. The study focused on patients with high-risk hematologic malignancies by ASBMT criteria, i.e., those with leukemia not in remission, lymphoma not achieving at least a partial response, or other disease under poor control undergoing allo-SCT. The trial was registered at Identifier: NCT01839916.

The study was approved by the Cancer Clinical Trials Review Committee and the Institutional Review Board at the University of Chicago. The primary objective of the clinical trial was to assess the tolerability of escalated dose pDLI as measured by the proportion of patients who received at least one pDLI. The secondary objective evaluated progression-free survival (PFS) at 2 years after transplantation. Correlative studies were also performed examining WT1 transcript number as a marker of residual disease after allo-SCT followed by pDLI receipt. T-cell receptor diversity (TCR) was evaluated to identify potential immune mechanisms underlying our findings.

Patients with hematologic malignancies undergoing T-cell depleted allo-SCT with matched related (MRD) or unrelated donors (MUD) were consented for pDLI administration prior to allo-SCT (Fig. 1). Patients with high-risk disease per ASBMT criteria were considered eligible. These criteria include refractory or relapsed acute myelogenous or lymphoid leukemia and recurrent or refractory malignant lymphoma or Hodgkin’s disease with less than a partial response at transplant. Exclusion criteria included pregnant or lactating females, Hepatitis B with positive viral load prior to transplant conditioning or Hepatitis C virus, Human Immune Deficiency Virus, psychiatric disease compromising the patient’s ability to give informed consent, or poor organ function.

Fig. 1

Clinical trial schema.

Steady-state donor lymphocytes were collected and cryopreserved in appropriate CD3+ enumerated aliquots. Lymphocytes collected later or from mobilized products were considered acceptable. Stems cells were subsequently collected following granulocyte-colony stimulating factor (G-CSF) mobilization. Allo-SCT was then performed with T-cell depleted conditioning regimens using alemtuzumab, 30–100 mg from Day 2 to 5 via IV administration. Immunosuppression with tacrolimus was withdrawn at day 60–75 post allo-SCT if no more than grade 1 acute (aGVHD) was present. It was recommended that the dose of immunosupression be reduced 25–50% every 5 days over a 10–20 day period and then be discontinued.

pDLI were then administered at day 75–90 and again in 4–8 week intervals. DLI doses were given based on the transplant donor. For patients with MRD: pDLI doses were 2 × 105 cells/kg; 5 × 105/kg; 1 × 106/kg; 2 × 106/kg; 5 × 106 kg. For patients with MUD: pDLI doses were 1 × 105/kg; 2 × 105/kg; 5 × 105/kg; 1 × 106/kg; 2 × 106kg. Prior to each pDLI, the patients were evaluated for acute and chronic GVHD and laboratory tests including complete blood count, comprehensive metabolic panel, and peripheral blood chimerism were obtained. At trial onset, patients who had either MUD or MRD SCT were enrolled. However, interim analysis after 59 patients showed that WOI was not feasible for MUD patients, and thus, only MRD patients were subsequently recruited.

For all patients, Armand Disease Risk Index categorization (DRI) was identified [15]. Patients continued in the study until disease relapse, inter-current illness preventing further treatment, unacceptable adverse events, patient withdrawal from the study, or at the investigator’s discretion. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria Scale. Immunologic data were also collected for WT1/ABL and TCR analysis as below.

Wilms Tumor 1 (WT1) and ABL gene PCR assay

Quantitative real-time PCR (qRT-PCR) was employed to assess the presence of minimal residual leukemia using transcript-specific primer and probe sets for WT1 and ABL genes (20 μM each primer: WT1 5′-CGGTCCGACCACCTGAAG/ 3′-TTCATCTGACCGGGCAAACT; ABL 5′-AAAATGACCCCAACCTTTTCG/3′-CCATTCCCCATTGTGATTATAGC (IDT Inc). 5 μM WT1 probe: 6FAM-CAGGTAAAACAAGTGAAAAGCCCTTCAGCTGT-TAMRA and 10 μM ABL: 6FAM-TCTAAGCATAACTAAAGGTGAAAAGCTCCGGGTCTT-TAMRA (Biosearch Technology, Inc)). The methodology for this analysis has been previously described [16]. Patient bone marrow and/or peripheral blood mononuclear cell complementary DNA (cDNA) samples synthesized from 5 μg RNA (RNAStat60, Teltest Inc) and template controls were assayed in triplicate using the LightCycler 480II (Roche). All transcript expression levels were determined by reference to standard curves generated from fivefold serial dilutions of K562 cell line cDNA (0.08–250 ng). The absolute transcript copy number was normalized to the endogenous control gene, ABL1.

TCR sequencing

TCR α and β-chain deep sequencing were performed to assess clonal enrichment of CD8+ T cells through pDLI administration using methodology that has also been described previously [17]. In brief, we performed PCR-based amplification of TCRA or TCRB gene products with adapter-conjugated primer sets. The template library was amplified by Nextera XT DNA sample prep kit (Illumina). Subsequently, the prepared library was analyzed using MiSeq Reagent 600-cycle kit v3 and MiSeq system (Illumina). After the deep sequencing, each V, (D), J, and C segments in the TCRA and TCRB reference sequences were assigned by determination of amino acid sequences of complement determining region 3 (CDR3). The diversity index (inverse Simpson’s index) in CDR3 sequences was calculated to assess overall diversity and clonality in the TCR clonotypes.

Statistical analysis

The OS and PFS for patients on study were estimated by means of Kaplan–Meier method, and were compared between patients with and without at least one pDLI with the use of log-rank test. The cumulative incidence method was used to estimate rates of aGVHD and non-relapse mortality (NRM). All statistical analyses were conducted using R software version 3.3.0.


Patient characteristics and treatment courses

Between June 1, 2013 and May 25, 2017, 75 patients (50 males, 25 female: ages, 20–75 years) underwent allo-SCT and were considered for pDLI. Patients had a variety of primary diseases: 37 AML, 11 MDS, 9 NHL, 9 ALL, 2 CML, 2 HL, and 5 other. Of the 75 patients, 29 were in remission and 46 were not (Table 1). The patients underwent SCT with 46 receiving an MRD transplant, and 29 receiving an MUD transplant. The patients undergoing transplantation received various conditioning regimens: 47 patients received a fludarabine/melphalan regimen, 26 received fludarabine/busulfan, and 2 received total body irradiation with etoposide. Patients in the trial had diverse range of Armand Disease Risk Index scores: 9 patients were deemed to be low risk, 51 intermediate, and 15 high risk. Alemtuzumab was used for T-cell depletion; 62 patients received a 100 mg dose and 13 received <100 mg (Table 1).

Table 1 Characteristics of the patients.

Withdrawal of immune suppression and treatment with pDLI

Fourty patients in the study were unable to undergo WOI and thus were ineligible for eventual pDLI due to a variety of co-morbidities or contraindications preventing WOI. Sixteen patients (40%) were unable to do so due to GVHD occurring prior to day 60, nine patients had early relapse (23%), eight patients had early deaths prior to WOI (20%), two patients had graft failure (3%), the study cut-off date was prior to Day 60 for two patients (3%) preventing WOI, and three patients were enrolled to another study (8%) (Table 2).

Table 2 The reasons why patients failed early WOI and pDLI administration.

Patients undergoing WOI were subsequently eligible for receipt of pDLI. Of the 28 MRD patients who were able to undergo WOI, 26 patients (93%) received at least 1 DLI, 16 patients (57%) received 3 or more pDLI, and 7 patients (25%) received all five planned pDLI (Table 3). Of the seven MUD patients able to undergo early withdrawal of immunosuppression, four patients (57%) received at least one pDLI, one patient (14%) received three DLI, and no patients received all five (Table 3). A greater proportion of MRD patients were able to undergo early WOI (p < 0.01) and receive at least 1 pDLI (p < 0.01), or received ≥3 pDLI (p < 0.01) as compared with MUD patients. Five patients who were able to undergo WOI did not receive any pDLI; four (80%) of these patients did not receive pDLI due to the development of GVHD after WOI, and one patient (20%) due to early death.

Table 3 The distribution of patients who were able to undergo early WOI and receive pDLI among the different donors.

Transplant and pDLI outcomes

Seventy-three of the patients undergoing allo-SCT (98%) achieved neutrophil engraftment by day 28. Median time to engraftment was 10 days (range, 8–31 days). Sixty-eight patients had platelet engraftment by day 28 (91%), and median time to recovery was 15 days (range, 10–31) (Table 4). NRM was 5% at 100 days and 16% at 1 year. Rates of aGVHD (Grades II–IV) at 1 year were 46 and 16% for chronic GVHD. One-year PFS was 51% (95% CI, 41–63%) and OS was 61% (95% CI, 51–73%) (Table 4). Thirty-nine patients had died at last follow up. Twenty-five patients (64%) died from relapse/progression, twelve patients died of infection or GVHD-related complications (31%), and two patients from other causes (5%) (Table 5).

Table 4 Transplant outcomes on the protocol.
Table 5 Cause of death for patients on the trial.

Median PFS for patients on the study was 366 days. Median OS was not reached. One-year NRM was 16% (95% CI, 9–25%). Rates of aGVHD at 1-year post-SCT (Grades II–IV) was 46% (95% CI, 33–57%).

Among the patients receiving at least one DLI on the study, median OS and PFS were not reached. One-year NRM was 3% (95% CI, 2–15%) and rate of aGVHD (Grades II–IV) at 1 year post allo-SCT was 28% (95% CI, 13–45%). The estimated 2-year PFS and OS rates for all patients were 41% (95% CI, 32–54%) and 51% (95% CI, 41–63%) compared with 57% (95% CI, 41–77%) and 67% (95% CI, 52–86%) for patients who received at least one pDLI (Fig. 2). We further assessed the PFS and OS of the subset of 26 patients who had MRD and received pDLI. Two-year PFS was 54% (95% CI, 38–77%) and 2-year OS was 65% (95% CI, 49–87%).

Fig. 2

OS and PFS of all the patients on the study and those who received pDLI.

PFS and OS were also calculated for patients with an intermediate disease risk index who received pDLI in the study. We subsequently compared these outcomes with those for intermediate risk patients who did not receive pDLI on the study. For intermediate DRI patients who received at least one pDLI in the study, 3-year OS was 50% compared with 31% for intermediate DRI patients who did not receive pDLI (p = 0.086). Three-year PFS for pDLI patients was 54% compared with 25% for intermediate DRI patients who did not receive a pDLI (p = 0.02) (Fig. 3).

Fig. 3

Comparison of PFS between patients with intermediate risk DRI receiving at least one pDLI vs no pDLI.

Immune reconstitution and DNA chimerism

DNA chimerism and immune reconstitution data were collected for all patients on the study. Patients receiving pDLI had higher percentages of donor chimerism in unfractionated blood and marrow as well as CD3+ chimerism at day 365 after allo-SCT compared with patients not receiving pDLI (data not shown). At 1 year, among patients receiving at least one pDLI, 95% of evaluable patients (20/21) had full donor chimerism compared with 59% (10/17) of those who did not. There was also a clear increment in chimerism with each pDLI.

pDLI was also associated with faster immune reconstitution post allo-SCT. There was a clear increase in rate of CD3+ cell count recovery, and total lymphocyte counts were higher at day 365 for patients receiving pDLI compared with those that did not. Similarly, CD19+ cell counts recovered faster for patients who received pDLI than for those that did not (data not shown).

Immunologic data

TCR diversity was assessed using peripheral blood samples from patients receiving pDLI. Blood samples were received for eight patients who had received a varying number of pDLI. Seven out of eight patients (88%) showed a decrease in TCR diversity index, which indicated clonal expansion of certain T-cell populations, after WOI and delivery of pDLI. Peripheral blood from 16 patients receiving pDLI was also assayed for WT1 and ABL copy number for assessment of minimal residual disease. Eleven out of sixteen patients (68%) showed that the WT1/ABL ratio diminished with sequential pDLI (data not shown).


Our trial demonstrates that for patients who have received an MRD allo-SCT, pDLI are tolerable beginning at day 75, and result in improved PFS, higher donor chimerism rates, and faster immune reconstitution. Moreover, pDLI can be given in an escalating dose format. Several prior studies have studied the use of pDLI in both retrospective and prospective fashion, however, our study is the first to systematically study and propose a particular dosing schedule.

Several prior studies have assessed pDLI use in a retrospective fashion and have shown positive clinical outcomes. Schmid et al. performed a retrospective registry analysis identifying 89 patients who received pDLI and found some benefit in OS for high-risk AML patients [6]. Their study, however, drew patients from different protocols without proscribed pDLI timing or doses. Jedlickova et al. similarly performed a retrospective analysis of a cohort of 46 AML patients receiving adjuvant DLI at two transplant centers after allo-SCT and found an OS benefit as compared with a control group [14]. The investigators in this study gave escalated doses of pDLI to patients similar to our protocol, however, no specific timing was set for the receipt of therapy and thus timing of pDLI receipt varied greatly. Wang et al. analyzed 123 patients with acute leukemia who received transplants from HLA identical donors and then subsequently received pDLI with improved survival [7]. In this study, the dosing of CD3+ and CD34+ cells given in pDLI varied greatly amongst the recipients and only one pDLI treatment was given to each patient.

In addition, several prospective trials have evaluated the use of pDLI and their effect on clinical outcomes, but do not present dose escalation protocols. Eefting et al. performed a prospective trial in 19 patients with ALL in which pDLI was given 6 months after transplant at specified doses, however, patients only received one pDLI [8]. Xuan et al. reported in 2016 on a prospective trial of 144 patients with refractory acute leukemia who received pDLI and found an OS benefit, however, again no dose escalation was performed [9]. Our study aligns with these trials and presents additional prospective data suggesting that PFS can be prolonged for patients with pDLI administration, however, our’s is unique in that a dose escalation strategy is presented as well.

There are several important findings in the trial. One is the evidence that our trial provides arguing against the use of pDLI in patients who have received MUD allo-SCT. Patients who had received an MUD transplant had increased rates of GVHD and thus were unable to undergo WOI or receive pDLI at the same rate as MRD patients. Interim analysis of our study revealed this trend and recruitment of MUD patients was halted. Our experience suggests that either pDLI should not be considered for MUD patients or different protocols should be studied to increase the tolerability of pDLI in this population. One potential area of future investigation is whether WOI can occur in a more protracted fashion and whether deployment of pDLI can occur later in the post-transplant course when risk of GVHD is lower. Retrospective data from our institution suggests that relapse most often occurs within 100 days and thus we designed our trial with the aim of having patients off immunosuppression and having received first DLI by day 100. As such, we employed a rapid WOI strategy with reduction of immunosuppresion by 25–50% every 5 days over a 10–20 day period at day 60–75 post allo-SCT. Future trials may consider a more gentle WOI strategy for MUD patients or perhaps aim for WOI at a later date.

Conversely, this study suggests that the use of pDLI should be more widely considered in the management of patients who received an MRD allo-SCT and provides a platform other centers can consider for when the intervention should occur. Additional directions for investigation could include an even further dose escalation study. The benefit of graft vs leukemia effect must be weighed against the risk of GVHD, but perhaps larger aliquots of pDLI could be tolerated and lead to deeper and more durable remissions.

An additional interesting immunologic finding was that multiple patients receiving pDLI had a diminishing TCR diversity index after DLI administration as compared with baseline. The narrow TCR index suggests the development of a clonal T-cell population, which could represent a subset of T cells that are carrying out a graft vs leukemia effect following pDLI administration.

The major limitation of our study is that a randomized trial was not performed. We attempted to create an effective control group as a comparator against the intervention group with the use of the Disease Risk Index categorization. The DRI groupings show that our results hold not just within our trial population, but against similar patients receiving treatment at our center.


This prospective trial demonstrates that early WOI followed by dose-escalation pDLI is feasible after alemtuzumab-based conditioning regimens for patients who have received MRD allo-SCT.


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HL was supported by UCCCC pilot grant, Cancer Research Foundation Young investigator award and K12 Paul Calabresi award. The work is also supported by University of Chicago Cancer Center Support Grant (CA014599).

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HL and AA designed the trial. HL, AA WS, RAL, OO, JK, JL, SK, PR, and MB conducted the clinical trial, collected and analyzed the clinic data. NF collected and prepared patient samples and performed WT1 qRT-PCR. JP and YN contributed to TCR sequencing. SL conducted the statistical analysis of the clinical results. All authors contributed to the data analysis and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hongtao Liu.

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While several co-authors had research support from pharmaceutical companies, or served as consultant or advisory board members for pharmaceutical companies, none has a conflict of interest associated with this current study.

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Kothari, S., Artz, A.S., Lee, S.M. et al. Dose escalation prophylactic donor lymphocyte infusion after T-cell depleted matched related donor allogeneic hematopoietic cell transplantation is feasible and results in higher donor chimerism, faster immune re-constitution, and prolonged progression-free survival. Bone Marrow Transplant 55, 1161–1168 (2020).

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