Biology of Blood and Marrow Transplantation
Volume 12, Issue 12 , Pages 1295-1301, December 2006

Safety and Efficacy of Donor Lymphocyte Infusions following Mismatched Stem Cell Transplantation

Department of Bone Marrow Transplantation & Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Received 28 March 2006; accepted 29 July 2006.

Article Outline

Abstract 

The use of a mismatched allograft necessitates T cell depletion for prevention of uncontrolled graft-versus-host disease (GVHD), thus impairing a graft-versus-leukemia effect. Data on donor lymphocyte infusion (DLI) after mismatched stem cell transplantation are lacking. Our experience with 28 patients (treated with 59 mismatched DLIs; range, 1-7) is described. The procedure was prophylactic in 6 patients (9 DLIs) and therapeutic in 22 (50 DLIs). DLI dose ranged from 102 to 1.5 × 109 T cells/kg. In the 6 patients receiving prophylactic DLI, complete remission was maintained in 5; however, 2 died from GVHD. Clinical response to therapeutic DLI was seen in 6 of 22 (27.3%) patients; a greater tumor burden produced a lower response. GVHD appeared in 13 of 28 patients. Surprisingly, a greater HLA mismatch was associated with a lower risk of GVHD, with 3 of 19 DLIs in 3/6 matching and 16 of 29 DLIs in 5/6 matching with similar follow-up. Nevertheless, no correlation between efficacy and HLA mismatching was noted. Death was frequent and usually related to the basic disease rather than to DLI complications. We conclude that mismatched DLI is feasible and may be effective, especially if given soon after transplantation. Future developments using cell therapy with selective or targeted anticancer activity are warranted, with special attention to prophylactic treatment of T cell depleted mismatched allografts recipients.

Key words: Graft-versus-host disease, Graft-versus-leukemia effects, Stem cell transplantation, Donor lymphocyte infusion, Mismatched

 

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Introduction 

The aim of allogeneic stem cell transplantation (SCT) is to combine tumor cytoreduction with optimal doses of chemoradiotherapy and to replace host with donor immunohematopoietic cells. Induction of host-versus-graft tolerance by engraftment of donor stem cells enables durable engraftment of immunocompetent donor lymphocytes, with subsequent induction of graft-versus-leukemia (GVL) effects expected to eliminate all residual chemoradiation-resistant malignant cells of host origin by alloreactive donor cells. For patients with no matched sibling available, a matched unrelated donor may provide an alternative treatment option. However, despite the growing number of volunteers in matched unrelated banks, for a large number of patients in need, a donor cannot be found and/or the search process is too long [1]. Successful use of a haploidentical mismatched family member donor may provide a donor for every patient in need at an optimal timing. As the technology improves and experience increases, the number of patients undergoing successful SCT from a mismatched related donor increases [2]. The use of a mismatched donor usually necessitates T cell depletion or positive selection of stem cells to prevent uncontrolled graft-versus-host disease (GVHD) [3]. Mandatory T cell depletion increases the risk of graft rejection due to loss of engraftment facilitating lymphocytes and decreases the intensity and efficacy of a GVL effect. Data on add back of donor lymphocyte infusion (DLI) after mismatched SCT done to correct these problems are lacking. We present our cumulative experience using DLI in a group of 28 recipients of mismatched allografts, with particular attention to the efficacy and toxicity.

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Methods 

Twenty-eight high-risk patients with hematologic malignancies that were treated with mismatched stem cell allografts followed by DLIs are described. Indications for transplantation and disease status are presented in Table 1, and tumor burden definitions are listed in Table 2. Patients were included if they had an indication for DLI after HLA-mismatched SCT without active GVHD, were off cyclosporine, and consented to participate in the clinical trial. Fifteen male and 13 female patients, with an range of 4 to 63 years (median, 21 years), participated. All patients were referred to the Hadassah Hospital (Jerusalem, Israel) for SCT between 1995 and 2003. Each participant signed an approved informed consent form. Fifteen patients received transplants from a parent, 9 from a sibling, 2 from unrelated donors (UDs), and 2 from other donors (Table 3). All DLIs were given from the original donor. Twelve patients received transplants from a 3/6 HLA-matched donor, 5 from a 4/6 HLA-matched donor, and 11 from a 5/6 HLA-matched donor. HLA typing method differed among family members serving as donors or UDs. In case of family donors, HLA-A and -B were typed using serologic methods and HLA-DR was typed using molecular methods. If matching higher then 4/6 was found, matched antigens were typed by molecular methods. In UDs, HLA-A, -B, and -DR were typed using molecular methods.

Table 1. Demographic Data of Mismatched DLI-Treated Patients
Diagnosisnpatients
Acute myeloid leukemia13
Acute lymphoblastic leukemia7
Chronic myeloid leukemia5
Other3
Hodgkin disease1
Non-Hodgkin lymphoma1
Myelodysplastic syndrome1
Indication for DLInprocedures
Prophylactic DLI (tumor burden 0)9
Therapeutic DLI (tumor burden 1-4)50
10
29
326
417

DLI indicates donor lymphocyte infusion.

Table 2. Definition of Tumor Burden
Tumor BurdenDefinition
0Complete remission, CML chronic phase
1Molecular relapse
2Cytogenetic relapse
3Hematologic relapse, CML blastic/accelerated phase
4Primary resistance to BMT

CML indicates chronic myeloid leukemia; BMT, bone marrow transplantation.

Table 3. Donor and HLA Matching Data
Patients, n
Donor relationships
Parent15
Sibling9
Unrelated2
Child1
Uncle1
Degree of match
3/6 HLA Antigens12
4/6 HLA Antigens5
5/6 HLA Antigens11

Conditioning used in most patients (n = 19) was a fludarabine-based myeloablative regimen. Other conditioning regimens were a fludarabine-based nonmyeloablative regimen (n = 3), a cyclophosphamide/total body irradiation-based myeloablative regimen (n = 4), and a busulfan myeloablative regimen (n = 2). GVHD prophylaxis used in patients with 5/6 HLA matching consisted of cyclosporine with/without methotrexate. In patients with lower matching, GVHD prophylaxis was done using T cell depletion.

The method of donor harvesting for DLI depended on the quantity considered necessary. In cases of low-dose DLI (≤106 T cells/kg), peripheral blood was used. High-dose DLI (>106 T cells/kg) was collected by leukapheresis using the Cobe (Gambro BCT, Lakewood, CO) spectra cell separator. T cell quantity in the graft was estimated by measuring the total number of lymphocytes in the graft multiplied by 0.7 (representing the average T cell proportion in peripheral blood). DLI dose and frequency differed according to HLA disparity, chimeric state, and disease activity. Basic dosing schedule was 4-6 weeks if grade >1 GVHD did not appear and an indication for DLI still existed. DLI for patients without evidence of disease (tumor burden, 0) was defined as prophylactic, whereas DLI for patients with evidence of disease (tumor burden, 1-4) was defined as therapeutic (Table 2). DLI effectiveness was defined as induction of remission.

Acute and chronic GVHD types were graded according to severity indices of the International Bone Marrow Transplantation Registry [4]. Immediately after the appearance of signs and symptoms of acute GVHD grade ≥2, intravenous methylprednisolone (2 mg/kg) was administered. Cyclosporine was added only if no control of GVHD could be achieved by methylprednisolone.

To assess degree of chimerism, minimal residual disease, and early relapse, patients were monitored at regular intervals by cytogenetic analysis and by donor- and host-specific DNA markers using male and female amelogenin gene polymerase chain reaction bands [5] and by variable number of tandem repeats/polymerase chain reaction assay [6].

Relapse was defined as recurrence of hematologic malignancy after the initial achievement of complete remission (CR). In patients who did not achieve remission of disease after transplantation, day 1 was considered for analysis as the day of relapse.

Mortality analysis was done with respect to the first DLI event, and GVHD analysis was done with respect to each DLI regardless of other DLIs given to the same patient. Statistical analysis included the Mann-Whitney test and Fischer exact test.

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Results 

DLI Procedures 

Fifty-nine DLIs were given to 28 patients at different intervals after SCT. The median time from SCT to DLI was 109 days (range, 1-984 days). Nine procedures were prophylactic for 6 patients with resistant overt disease at time of transplantation (but in CR at time of DLI, including 3 patients with chronic myeloid leukemia [CML], 2 with acute myeloid leukemia [AML], and 1 with myelodysplastic syndrome) and 50 were therapeutic for treatment of relapse (Table 2). Time from transplantation to relapse was 1-361 days (median, 83 days). Most patients had documented full (n = 16) or partial (n = 6) donor cell engraftment before DLI. Thirteen patients received >1 DLI (range, 1-7 DLIs; median, 1 DLI/patient). DLI dose ranged from 102 to 1.5 × 109 calculated T cells/kg (median, 1 × 107 calculated T cells/kg). In principle, lower doses were given to patients with a lesser tumor burden, whereas higher doses were given to patients with a greater tumor burden (Table 2).

DLI Efficacy 

Six patients received prophylactic DLIs (HLA matching 3/6 in 4 patients, 4/6 in 1 patient, and 5/6 in 1 patient). Only 1 patient relapsed and 3 of them are alive in continuous CR.

Therapeutic DLIs were given to 7 patients with tumor burden 4, 12 patients with tumor burden 3, and 3 patients with tumor burden 2. Clinical response to DLI was seen in 6 of 22 (27.3%) patients including those in CR (n = 4), those with a hematologic response (n = 1), and those in partial remission (n = 1; Table 4). Three of the 22 patients who received therapeutic DLIs survived to time of analysis, 1 with tumor burden 4 and 2 with tumor burden 3. Only 1 of these patients is in continuous CR. Cause of death was mainly due to disease progression. GVHD-related mortality is reported below.

Table 4. Patients’ Disease Status, DLI Treatment, and Response
UPNBasic diseaseHLA matchDLI indicationDLI doses (T cells/kg)CR achievedGVHDGradeStatus at analysis
1169CML3Prophylactic104NAYes2A&W
1462AML3Prophylactic104NAYes4Dead
1747AML3Prophylactic7.6 × 104, 1.9 × 106NAYes1A&W
1777MDS3Prophylactic1.7 × 106, 2.45 × 107NA——Dead
1336CML4Prophylactic105NA——A&W
1138CML5Prophylactic5.6 × 108, 105, 2 × 106NAYes3Dead
941AML3Resistant1.6 × 107No——Dead
1055AML3Relapse103, 103No——Dead
1068AML3Relapse4.3 × 107No——Dead
1122ALL3Relapse5 × 107No——Dead
1153AML3Relapse106No——Dead
1514ALL3Resistant106, 106No——Dead
1773AML3Resistant8.2 × 105No——Dead
1874AML3Resistant104, 3.4 × 106, 2.5 × 105, 3.13 × 107No——Alive
1126AML4Relapse105No——Dead
1350ALL4Resistant9 × 105, 3.6 × 107, 2.7 × 107, 107, 7.9 × 107No——Dead
1587ALL4Relapse102, 104, 107No——Dead
1813ALL4Relapse106Temporary CRYes4Dead
930AML5Relapse105Hematological response——Dead
950HD5Relapse1.4 × 107NoYes2Dead
957AML5Relapse2 × 106PRYes2Dead
1036CML5Relapse3.2 × 108YesYes3Dead
1374AML5Relapse1.78 × 107, 3.14 × 108No——Dead
1517ALL5Relapse3.27 × 107YesYes1Dead
1599AML5Relapse3.1 × 108NoYes4Dead
1595NHL5Persistent1.57 × 107, 108, 108NoYes2Dead
1607CML5Relapse1.1 × 106, 5.6 × 107, 5.2 × 106, 106, 1.9 × 107, 5.2 × 107, 106YesYes3A&W
1757ALL5Relapse8.8 × 107, 1.53 × 109, 105, 3.7 × 108, 6 × 107, 1.05 × 109NoYes1Alive

DLI indicates donor lymphocyte infusion; UPN, unique patient number; CR, complete remission; GVHD, graft-versus-host disease; CML, chronic myeloid leukemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; NA, not applicable; A&W, alive and well.

Role of Mismatched DLI on GVHD 

Thirteen of 28 patients had GVHD before DLI (median peak grade, 2; range, 1-3); in most cases, GVHD subsided before DLI.

After DLI, signs of acute GVHD appeared after 20 of 59 DLI procedures and in 2 cases (7 DLI procedures) clinical features of chronic GVHD were apparent. The median acute GVHD grade was 2 (range, 1-4; Table 4). Time from DLI to onset of clinically overt GVHD ranged from 7 to 155 days (median, 27 days). GVHD was observed after 3 of 19 DLI procedures among recipients of 3/6 mismatched allografts, 1 of 11 DLI procedures among recipients of 4/6 mismatched allografts, and 5 of 6 DLI procedures among recipients of 5/6 mismatched allografts (P = .002; median follow-ups, 187, 299, and 192 days, respectively). Risk of GVHD development was higher with prophylactic DLI (66.7%) than with therapeutic DLI (28.0%; median follow-ups, 630 and 94 days, respectively; P = .03). In addition, greater tumor burden lowered the risk of GVHD, with 3 of 7 cases observed among DLI recipients treated for grade 2 tumor burden and 10 of 26 and 1 of 17 cases observed among patients with tumor burdens of 3 and 4, respectively (P = .007). Using the Mann-Whitney test, no correlation was found between the dose of DLI and the appearance of GVHD. No correlation to GVHD was found when a cutoff level of 105 calculated T cells/kg was used. There was no significant effect of DR mismatch on the appearance of GVHD.

Procedure-Related Mortality 

At the time of analysis, 22 patients died and 6 were alive. Median follow-up from the first DLI was 41 days (range, 7-1629 days). Survivors were 3 of 5 patients with CML, 2 of 13 patients with AML, and 1 of 7 patients with acute lymphoblastic leukemia (ALL; P = .033). The patient with ALL was alive but with active disease at time of analysis. Cause of death in 2 patients with CML was related to DLI complications, whereas only 1 of 11 patients with AML and no patients with ALL died from DLI complications (P = .017). Cause of death for the remaining patients was related to disease progression. No significant difference in mortality was found within the different HLA matching groups (Figure 1). However, when the interval between DLI to death within different HLA-mismatched groups was analyzed, we found that a greater degree of mismatch shortened survival after DLI, with 27, 53, and 132 days for recipients with 3/6, 2/6, and 1/6 HLA mismatching, respectively (P = .033). Three of the 6 patients who received prophylactic DLI survived, whereas 19 of 22 patients treated with therapeutic DLI died (P = .09). The Mann-Whitney test showed only a trend toward significance, with a higher dose of DLI increasing risk of death (P = .103). Using 105 calculated T cells/kg as a cutoff again produced only a trend toward higher risk of death (P = .09).

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Discussion 

Allogeneic SCT represents an important therapeutic tool for the treatment of an otherwise incurable broad spectrum of malignant and nonmalignant diseases. Preclinical and clinical studies have indicated that much more effective eradication of a host immunohematopoietic system or malignant cells can be mediated by alloreactive donor lymphocytes in the process of adoptive allogeneic cell therapy after SCT [7, 8, 9]. Thus, eradication of all malignant cells can be accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy [10, 11]. The major risk of DLI is the development of acute and chronic GVHD types that may occur in 20%-60% of patients [11, 12, 13], leading to significant morbidity and mortality even after treatment with fully matched donor lymphocytes. Scanty reports on mismatched unmanipulated DLI exist in the literature. Kawano et al [14] reported on 4 patients who received transplants from HLA-mismatched donors who received prophylactic DLI. All developed acute GVHD (3 of 4 patients with GVHD grade >2) and all died 56-363 days after transplantation (death due to relapse, multiorgan failure, and GVHD). Klingebiel et al [15] reported their experience with haploidentical SCT for childhood ALL. Ten of the 27 reported patients were treated with DLI (dose not mentioned) and 4 developed acute GVHD, maximum grade 3. Outcome of these patients was not reported. In another study, DLI was administered to recipients of unrelated, T cell depleted, stem cell allografts, and it was found that only HLA mismatching was associated with a higher incidence of grade ≥2 acute GVHD and mortality due to acute GVHD. Eighteen of 20 (90%) recipients of mismatched and 53 of 86 (62%) recipients of matched allografts developed grade ≥2 GVHD (P = .01); of these, 9 (50%) recipients of mismatched and 8 (15%) recipients of matched stem cell allografts died of acute GVHD (P = .003). Neither the GVHD risk group nor the number of T cells infused was significantly associated with acute GVHD. However, there was only 1 HLA locus mismatched in these patients [16]. Some other less informative case reports of recipients of mismatched DLI exist in the literature [17, 18, 19].

In this report, we have described the Hadassah experience in a high-risk cohort of recipients of mismatched DLI, prophylactically and therapeutically, with hematologic malignancies. We have shown that prophylactic DLI was significantly more effective than therapeutic DLI but carried a higher risk of GVHD. As previously described for recipients of matched stem cells and DLI [10, 20, 21], in patients who received therapeutic DLI, a greater tumor burden lowered the response. In parallel, possibly also partly explaining this conclusion was the observation that a greater tumor burden lowered the risk of GVHD. Other possible explanations for this phenomenon is a downregulation of antihost alloreactivity caused by tumor cells by acquired tolerance of allogeneic minor histocompatibility antigens [22] or the presence of apoptotic cells (common in proliferating tumors) that induce a transforming growth factor β-dependent regulatory T cell expansion [23]. Due to the small number of patients with GVHD, we could not assess the effect of anti-GVHD treatment on the GVL effect. GVHD appeared in <50% of patients. Surprisingly, a greater HLA mismatch lowered the risk of severe GVHD, with 3 of 19 DLIs in recipients of 3/6 mismatched allografts and 16 of 29 DLIs in recipients of 5/6 mismatched allografts with similar median follow-ups (187 and 192 days, respectively). Only 1 patient showed evidence of graft rejection, thus excluding the possibility that the reason for lower risk of GVHD in the other patients was rejection of lymphocytes. Death was frequent and usually related to progression of the basic disease rather than to DLI-induced complications. However, time to death, but not overall mortality, was significantly shorter with greater HLA mismatch.

Our results justify the use of cell therapy after transplantation of mismatched stem cells in CML and AML. Unfortunately, no success could be documented in our series with the limited number of patients with ALL. However, it should be remembered that development of GVHD after transplantation of mismatched alloreactive T cells required immediate anti-GVHD treatment, thus negating the GVL effects inducible by alloreactive T cells. Because GVL effects are time consuming even in patients with CML, which is slowly progressing disease [24], whereas tumor progression in patients with relapsed chemoresistant ALL is fast, it seems reasonable to apply DLI in ALL prophylactically against a low tumor burden, or as soon as the first sign of molecular rather than overt hematologic relapse is demonstrable, because, in principle, patients with ALL can respond to immunotherapy with DLI [10, 21]. Due to the limited number of patients, no analysis could have been performed regarding the effect of anti-GVHD treatment after DLI (when given) on GVL effects.

Based on the data and considering the cumulative international experience, it appears that development of safer cell therapy procedures with less aggressive and more selective anticancer effects are urgently required, particularly for recipients of mismatched stem cell allografts and other recipients of T cell depleted allografts. Such safer strategies should focus on more selective targeting of specifically immune T cells and recombinant interleukin-2-activated natural killer cells [25, 26, 27, 28, 29, 30, 31, 32] rather than using nonselective and hazardous nonspecific T cell therapy or antibody-guided recombinant interleukin-2-activated lymphocytes [33]. The use of anticancer effector cells devoid of GVHD capacity may enable induction of effective GVL effects without blocking reactivity of alloreactive lymphocytes with immunosuppressive agents indicated to control GVHD. One promising approach currently under investigations involves the use of activated, intentionally mismatched CD3-depleted, CD56-positive natural killer cells [27, 28].

In conclusion, the development of safer and more effective cell-mediated immunotherapy for patients with leukemia resistant to all available anticancer modalities remains a challenge. Maximizing antitumor effects and minimizing antihost reactivity remain the gold standard awaiting innovative methods to control alloreactivity or, preferably, selective antitumor reactivity of donor lymphocytes.

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Acknowledgments 

We thank Prof Arnon Nagler for devoted work while in working in our center. We also thank the Danny Cunniff Leukemia Research Laboratory, the Gabrielle Rich Leukemia Research Foundation, the Cancer Treatment Research Foundation, the Novotny Trust, the Szydlowsky Foundation, the Fig Tree Foundation, and Ronne and Donald Hess for continuous support of our ongoing basic and clinical research.

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PII: S1083-8791(06)00519-2

doi:10.1016/j.bbmt.2006.07.014

Biology of Blood and Marrow Transplantation
Volume 12, Issue 12 , Pages 1295-1301, December 2006

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