Graft-Versus-Host Disease

Administration of short-term immunosuppressive agents after DLI reduces the incidence of DLI-associated acute GVHD without influencing the GVL effect

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Abstract

Donor lymphocyte infusion (DLI) exerts a GVL effect, but its use is limited by a high incidence of GVHD. We retrospectively evaluated the efficacy of administering short-term immunosuppressive agents for prophylaxis against DLI-associated acute GVHD, and its influence on the GVL effect. Seventy patients with leukaemia received G-CSF primed DLI after HLA-identical sibling haematopoietic stem cell transplantation (HSCT) for treatment or prophylaxis against leukaemia relapse. Short-term immunosuppressive agents were given to 54 patients for prophylaxis against DLI-associated acute GVHD. Seventeen patients experienced acute GVHD; 30 patients developed chronic GVHD; and no GVHD-related death was observed. A significant difference was observed between the group that did not receive prophylaxis against GVHD or received prophylaxis for less than 2 weeks and the group that received prophylaxis for over 2 weeks (CsA or MTX at 10 mg/week) with regard to the incidence of DLI-associated acute GVHD (14/28 vs 3/42, P=0.000); no difference was observed in the relapse rate for prophylactic DLI patients between the two groups (4/10 vs 12/29). Using immunosuppressive agents for 2–4 weeks may reduce DLI-associated acute GVHD without influencing relapse and survival after G-CSF-primed DLI.

Introduction

Adult patients who develop advanced haematologic malignancies have a poor prognosis even after allogeneic haematopoietic stem cell transplantation because of a high rate of relapse and transplant-related mortality.1, 2 Donor lymphocyte infusion (DLI) exhibits definite anti-leukaemia effects in these patients.3 It is also known that DLI could be followed by a high rate of severe GVHD and, occasionally, pancytopenia and infection.4, 5 In our previous study, it was found that infusion of G-CSF-primed peripheral blood progenitor cells (GPBPC) instead of non-primed lymphocytes exhibited a comparative or stronger GVL effect and comparatively low incidence of GVHD, which is rarely complicated with pancytopenia.6, 7 When DLI with GPBPC is combined with the use of short-term immunosuppressants such as short-term CsA or MTX for GVHD prophylaxis, the incidence of fatal GVHD complicated with DLI may be further reduced.8, 9 In our recent report, six patients experienced II–IV grade acute GVHD after 39 modified prophylactic DLIs in 33 patients following HLA-identical HSCT.10 However, whether the use of immunosuppressants after modified DLI would alter the GVL effect while reducing the incidence of fatal GVHD is still unknown. The current study was initiated to retrospectively evaluate the appropriate duration of administration of short-term immunosuppressive agents for reducing the incidence of acute GVHD without abrogating the GVL effect of DLI.

Patients and methods

Eligibility criteria

From January 1991 to June 2007, 70 patients with leukaemia who received modified DLI (GPBPCs instead of steady donor lymphocytes) from their initial donors for the treatment or prophylaxis of leukaemia relapse consecutively after HLA-identical sibling HSCT were included in this study. Nine of 31 patients receiving therapeutic DLI were reported in 2003;7 twelve and 33 of 39 patients receiving prophylactic DLI were reported in 20068 and 2008;10 and these patients were further followed up in this study. Patient characteristics are summarized in Table 1.

Table 1 Characteristics of patients and grafts

Transplant procedure

Transplant procedures including conditioning regimen, prophylaxis of GVHD, stem cell collection and supportive care were described in our previous report.10 All patients received myeloablative conditioning with TBI and CY (TBI/CY, n=9) or the modified BU-CY regimen (mBuCy, n=61). The source of stem cells was G-CSF-mobilized PBSCs for 33 patients and a mixture of G-CSF-mobilized bone marrow cells and G-CSF-mobilized PBSCs for the other 37 patients.

Protocol of DLI

All patients received modified DLI, that is, GPBPCs were infused instead of steady donor lymphocytes. The Peking University Review Board approved the cryopreservation, remobilization, and infusion of GPBPCs. All donors and patients gave signed consent.

Therapeutic DLI

DLI was administered for the treatment of leukaemia relapse after transplantation. When haematologic or cytogenetic relapse of leukaemia was diagnosed, immunosuppressive agents were discontinued with or without prior intervention. Acute leukaemia patients whose blast count in bone marrow at the time of relapse after HSCT was over 20% received prior chemotherapy and CML patients in haematologic or cytogenetic relapse received prior imatinib. DLI was given 48 h after the last chemotherapy dose or 1 month after the first imatinib dose.

Prophylactic DLI

DLI was planned from days 30 to 120 after transplantation for the prevention of leukaemia relapse, before haematologic relapse was diagnosed in very high-risk patients (patients with acute leukaemia in the non-remission state or CML in blast phase), or patients with mixed chimerism, or patients with signs of minimal residual disease. Before DLI, serious infection had to be cleared. No early deaths, recurrence of leukaemia or GVHD were accepted or GVHD had to be controlled with no serious organ failure present. For patients receiving DLI before day 90 post transplantation, the original CsA treatment was continued for another 2 weeks after the infusion, and then tapered and discontinued within 4 weeks if no DLI-associated GVHD occurred. For patients receiving DLI after day 90, immunosuppression was discontinued for a minimum of 2 weeks and no active GVHD was present before DLI. These patients took oral CsA or MTX (MTX, at a dose of 10 mg, repeated at day 8 after the first dose and then at weekly intervals), for 2–4 weeks after DLI for the prevention of DLI-associated GVHD.

More than one DLI could be administered if persistent minimal residual disease existed without any signs of GVHD after DLI in these patients. The initial mononucleated cells (MNCs) for DLI (therapeutic or prophylactic) and the dose of cells for repetitive infusion were 1 × 108 MNCs/kg. DLI doses were also defined as CD3 cells per kilogram of recipient weight.

Prophylaxis of GVHD after DLI

From January 1991 to August 2002, no immunosuppressive agents were used to prevent GVHD in the initial 16 patients, and after September 2002, immunosuppressive agents were planned to be given for 2–6 weeks at the discretion of the attending physicians mainly according to patients’ disease status and minimal residual disease status before and after DLI. Among 28 patients receiving prophylactic DLI before day 90 post transplantation, the original CsA treatment was discontinued immediately after DLI in the initial four patients and discontinued within 2 weeks after DLI in five patients due to advancement of leukaemia; For the other 42 patients receiving prophylactic DLI after day 90 or therapeutic DLI, 12 patients had no immunosuppression and seven patients were given CsA or MTX for less than 2 weeks after DLI.

Therapy of DLI-associated GVHD

This was described in a previous report.10

Evaluations and definitions

The severity of acute and chronic GVHD was diagnosed based on the standard criteria.11 However, GVHD was diagnosed as acute or chronic according to the clinical features of the affected organs rather than the time elapsed after DLI. Donor chimerism in unfractionated bone marrow before and after DLI was compared using FISH in gender-mismatched transplants and short tandem repeat analysis in gender-matched transplants.

High-risk leukaemia was defined as (1) acute leukaemia in the first CR (CR1) with an unfavourable cytogenetic abnormality, such as a positive Ph; (2) acute leukaemia more than CR2 status or in the non-remission state (including primary induction failure, which is defined as non-remission after 2 or more cycles of chemotherapy, and untreated or refractory relapse); (3) CML in accelerated phase or BP.

Haematologic relapse of leukaemia after transplantation was defined as the recurrence of the signs and symptoms of leukaemia, by reappearance of blasts in peripheral blood or BM infiltration by more than 5% of blasts in a representative smear. Extramedullary relapse was defined by any manifestation of leukaemia outside the haematopoietic system. In CML or Ph+ acute leukaemia, cytogenetic relapse was defined as the recurrence of metaphases with the Ph+ without exhibiting the haematologic or clinical features of CML.

Statistical analysis

Numeric variables were analyzed as categories by considering their value below or above the median of the entire cohort, as indicated in Results. The time elapsed between the onset of GVHD and DLI was defined as the time from DLI to the onset of any grade of GVHD. When groups were compared according to continuous covariates, we calculated the median of each group and Mann–Whitney U-tests were used. A χ2-test was used to compare categoric covariates; stepwise logistic regression was used for multivariate analysis. The cumulative incidence of acute and chronic GVHD after DLI was calculated by taking into account the competing risk of death. Distributions for time to relapse, time to CR, OS and LFS were evaluated using the Kaplan–Meier analysis. The log-rank test and a Cox proportional hazard regression model were used for analysis of risk factors for time-to-event variables. Surviving patients were followed up, and the results of the follow-up examinations were analyzed on 1 December 2007. Unless otherwise specified, all the reported P-values were based on two-sided hypothesis tests. The SPSS and R software packages were used for data analysis.

Results

Cell count and chimerism

The cell subsets infused for DLI including CD3 cell compartment are shown in Table 1. Chimerism analysis indicated that all patients achieved full donor chimerism after DLI.

Short-term immunosuppression reduces the incidence of acute GVHD after DLI

Comparisons of patient and graft characteristics between no/short post-DLI prophylaxis vs long (that is, greater than 2 weeks) are shown in Table 1. The incidences and onset time of acute GVHD are shown in Table 2.

Table 2 Effect of duration of GVHD prophylaxis on incidence of GVHD after DLI

All patients who developed acute GVHD after DLI were controlled after CsA was adjusted to an effective concentration or substituted by FK506 plus MP or monoclonal antibodies against CD25 or MTX. All cases of chronic GVHD were controlled, and no GVHD-related deaths occurred.

A total of 92 infusions were administered to 70 patients. Ten patients received these two times and six patients three times; there were no signs of acute GVHD after the second or third infusions.

In terms of predictors for actual and cumulative incidences of acute GVHD, the incidences were much higher in the no/short immunosuppression group than in the long immunosuppression group (P<0.001 and P=0.01, respectively, Table 2 and Figure 1). Multivariate analysis showed that the significant factor associated with lower incidences of acute GVHD was the use of immunosuppressive agents for over 2 weeks (P=0.001); the incidence was not related to age (P=0.66), sex (P=0.62), conditioning regimen (P=0.27), administration of DLI after day 90 following HSCT (P=0.15) or disease type (P=0.18). For actual and 100-day cumulative incidences of chronic GVHD, the incidences were comparable in groups of no/short and long immunosuppression (8/25 vs 22/42, P=0.131 and 34.5 vs 41.7%, P=0.195, respectively).

Figure 1
figure1

The influence of duration of GVHD prophylaxis on occurrence of acute GVHD after DLI. The cumulative incidence of acute GVHD was indicated along the DLI time. Acute GVHD occurred in nine of 16 patients receiving no immunosuppressive agents, five of 12 patients receiving immunosuppressive agents for less than 2 weeks, three of 35 patients receiving immunosuppressive agents for 2–4 weeks, and none of seven patients receiving immunosuppressive agents for over 4 weeks (Grey test: P=0.0099). Patients receiving no immunosuppressive agents was shown as solid line (——), patients receiving immunosuppressive agents for less than 2 weeks was shown as dashed line (- - -), patients receiving immunosuppressive agents for 2–4 weeks was shown as dotted line (), and patients receiving immunosuppressive agents for over 4 weeks was shown as dot-dash line (- ·).

Short-term immunosuppression did not influence the GVL effect

As of 1 December 2007, after a median follow-up period of 18 months (range, 1.8–199 months), 46 patients experienced haematologic or extramedullary relapse at a median of 85 days (range, 20–1751 days) after transplantation.

Thirty-one patients were diagnosed with haematologic or extramedullary relapse of leukaemia at a median of 73 (20–1751 days) days after HSCT, prior to DLI. Among these 31 patients, 15 with high-risk leukaemia did not receive prophylactic DLI because of GVHD (n=4), infection (n=2), or early relapse (n=9). As shown in Table 3, patient characteristics were relatively balanced between the two groups of no/short (18 patients) and long (13 patients) immunosuppression. Responses to therapeutic DLI are shown in Table 3. The 5-year OS and LFS in the no/short or long immunosuppression group were 33 vs 90% with P=0.001 and 33 vs 83% with P=0.003, respectively (Table 3). There is a significant difference in LFS between the group with or without prior intervention (33 vs 56%, P=0.042). Multivariate analysis showed that the significant factors associated with a higher LFS were prior intervention before DLI (P=0.021), remission status before transplantation (P=0.030) and the development of DLI-associated chronic GVHD (P=0.048); However, LFS rates were not associated with the treatment involving no/short or long immunosuppression (P=0.071), the development of DLI-associated acute GVHD (P=0.435), type of disease (P=0.143), or time from HSCT to relapse (P=0.116).

Table 3 Response to therapeutic DLI

Sixteen of 39 patients receiving prophylactic DLI were diagnosed with haematologic or extramedullary relapse of leukaemia at a median of 90 (40–420 days) days after HSCT. The median interval from the first and last DLI to the onset of relapse was 47 days (range, 11–318 days) and 33 days (range, 6–241 days), respectively. As shown in Table 4, patient characteristics were relatively balanced between the two groups of no/short (10 patients) and long (29 patients) immunosuppression. Responses to prophylactic DLI are shown in Table 4. Four of the 16 relapsed patients were in the no/short immunosuppression group and the other 12 were in the long immunosuppression group (4/10 vs 12/29, P=0.62). The differences in the duration of immunosuppression at the cumulative relapse rate and OS between the two groups were not significant (P=0.752 and P=0.198, respectively, Table 4). Early relapse (within 1 year from HSCT) is associated with lower OS rate (P=0.000).

Table 4 Response to prophylactic DLI

In terms of predictors for cumulative incidences of relapse rate, multivariate analysis showed that the significant factor associated with lower relapse rate was chronic GVHD (P=0.007); However, relapse rates were not associated with the treatment involving no/short or long immunosuppression (P=0.507), remission status before transplantation (P=0.449), type of disease (P=0.087), age (P=0.144), the source of stem cells (P=0.880), or the development of DLI-associated acute GVHD (P=0.829).

Follow up and outcome

As of 1 December 2007, 18 of 39 and 13 of 31 patients had survived without recurrence of their original leukaemia after prophylactic or therapeutic DLI. The estimated 1.5-year OS were 47 and 58%, respectively. The LFS rates were 47 and 56%, respectively. The causes of death were leukaemia relapse (n=21), infections (n=12), GVHD in combination with infections (n=2), and haemorrhage (n=1).

Discussion

To maximize the GVL effect, DLI is usually administered without immunosuppressive agents.12 Thus, the incidence of acute GVHD after DLI is reported to be 49–91%.4, 9 To minimize the incidence of acute GVHD after DLI, several approaches have been tried in many reports, such as sequential T-cell dose escalation13, 14 and the use of GPBPCs instead of steady-state donor lymphocyte harvests for the infusion.6 Several reports including our own data indicate that in vivo G-CSF use indirectly induces a decrease in T-cell proliferation and type II helper T-cell polarization of the cytokine profile.15, 16, 17, 18 This may help to provide a biological explanation for lower occurrence of aGVHD following GPBSC than that of DLI. In the current study, acute GVHD after GPBPC infusion occurred in 9 of 16 patients without immunosuppression. However, the incidence of acute GVHD after GPBPC was still high. Alternative measures need to be explored to further reduce the incidence of acute GVHD after DLI. For the first time, the current study suggested that, compared with the group without or with less than 2 weeks post DLI prophylaxis, the use of short-term CsA or MTX for over 2 weeks after GPBPC infusion can significantly reduce the incidence of acute GVHD without affecting the incidence of chronic GVHD in HLA-matched HSCT (Table 2 and Figure 1). This may be associated with both the use of GPBPC and short-term CsA or MTX administration for prophylaxis against GVHD. Our recently published data also indicate that in HLA-mismatched HSCT settings, there was a significant difference in the incidence of acute GVHD after DLI between the group that did not receive immunosuppressive agents and the group that received CsA or MTX for 2–4 weeks (5/9 vs 1/11, P=0.013).9 As characteristics of patients and grafts between the two groups were comparable in the present study (Table 1), at the very least, our results suggest that post DLI immunosuppression is relatively safe in terms of aGVHD.

For the first time, the current report attempts to determine whether the GVL effect was also reduced. LFS rate after therapeutic DLI for relapsed patients who received no/short GVHD prophylaxis was lower than that in patients who received long prophylaxis. This is more likely to be due to patient diagnoses and pre-DLI therapy, rather than DLI or GVHD prophylaxis. The therapeutic group that received long GVHD prophylaxis comprised nine CML patients who received imatinib before DLI, and four acute leukaemia patients including two ALL patients; the group that received no/short prophylaxis comprised 5 CML patients who received imatinib before DLI, and 13 acute leukaemia patients including 7 ALL patients. Numerous studies have shown that DLI has a positive effect on GVL for early stage CML patients, especially when combined with imatinib19, 20 but does not have an adequate GVL effect in ALL.3, 5 Multivariate analysis has shown that the significant factor associated with higher LFS rate was prior intervention before DLI. Collins et al.21 reported that the use of chemotherapy and PBPC could provide a faster response than DLI alone to result in a median time to remission of 34 days in ALL and 85 days in CML. This is also in concordance with Sohn's report22 and results of the recent EBMT data.23 Despite these factors, the results at least suggested that the GVL effect might not be reduced by immunosuppression. Moreover, preliminary results showed that the relapse rate with prophylactic DLI was comparable between the two groups, as shown in Table 4. One of the possible explanations is that short-term GVHD prophylaxis reduced the incidence of acute GVHD without affecting the incidence of chronic GVHD. Numerous studies including our present study have shown that chronic GVHD is the most important factor for long-term remission,9, 23 but relapse rate was not associated with the development of acute GVHD. Thus, short-term GVHD prophylaxis did not reduce the GVL effect, as it did not affect the incidence of chronic GVHD. Considering the non-randomized nature of the report and practise changes over time, other mechanism by which short-term GVHD prophylaxis reduces the incidence of acute GVHD without influencing the GVL effect need to be further explored; but at the very least, this suggests that prophylactic immunosuppression did not abrogate the GVL effect.

In conclusion, G-CSF-primed DLI combined with CSA or MTX at 10 mg/week for 2–4 weeks can reduce DLI-associated acute GVHD without influencing relapse and survival. This strategy might further improve the safety and efficacy of DLI. Prospective studies are required to confirm the results, and the mechanisms require further exploration.

Conflict of interest

The authors declare no financial conflict of interest.

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Acknowledgements

We thank Enpapers Team for critically reviewing this paper in English. This work was supported by the National Outstanding Young Scientist's Foundation of China (Grant no. 30725038), Hi-tech Research and Development Program of China (Grant no. 2006AA02Z4A0), Program for Innovative Research Team in University (Grant no. IRT 0702), Scientific Research Fund for Capital Medicine Development (Grant no. 2006-1010) and Leading Program of Clinical Faculty accredited by the Ministry of Health of China.

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Correspondence to X-J Huang.

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Keywords

  • donor lymphocytes infusion
  • relapse
  • GVHD
  • transplantation

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